Proposed Re-evaluation Decision PRVD2019-10

Pyriproxyfen and Its

Associated End-use

Products

Consultation Document

(publié aussi en français) 6 November 2019

This document is published by the Health Canada Pest Management Regulatory Agency. For further

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ISSN: 1925-0959 (print)

1925-0967 (online)

Catalogue number: H113-27/2019-10E (print)

H113-27/2019-10E-PDF (PDF version)

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Proposed Re-evaluation Decision – PRVD2019-10

Table of Contents

Proposed Re-evaluation Decision ................................................................................................... 1

Outcome of Science Evaluation................................................................................................... 1

Proposed Regulatory Decision for Pyriproxyfen ......................................................................... 2

International Context ................................................................................................................... 2

Next Steps .................................................................................................................................... 3

Science Evaluation .......................................................................................................................... 4

1.0 Introduction ......................................................................................................................... 4

2.0 Technical Grade Active Ingredient ..................................................................................... 4

2.1 Identity ........................................................................................................................ 4

2.2 Physical and Chemical Properties .............................................................................. 4

2.3 Description of Registered Pyriproxyfen Uses ............................................................. 5

3.0 Human Health Assessment ................................................................................................. 5

3.1 Toxicology Summary ................................................................................................. 5

3.1.1 Pest Control Products Act Hazard Characterization .................................................. 9

3.2 Dietary Exposure and Risk Assessment ................................................................... 10

3.2.1 Determination of Acute Reference Dose .................................................................. 11

3.2.2 Acute Dietary Exposure and Risk Assessment ......................................................... 11

3.2.3 Determination of Acceptable Daily Intake ................................................................ 11

3.2.4 Chronic Dietary Exposure and Risk Assessment ...................................................... 12

3.2.5 Cancer Assessment ................................................................................................... 13

3.3 Exposure from Drinking Water ................................................................................ 13

3.4 Occupational and Non-Occupational Exposure and Risk Assessment ..................... 13

3.4.1 Toxicology Reference Values ................................................................................... 13

3.4.2 Residential Exposure and Risk Assessment ............................................................. 14

3.4.3 Occupational Exposure and Risk Assessment .......................................................... 17

3.5 Aggregate Exposure and Risk Assessment ............................................................... 20

3.5.1 Toxicology Reference Values for Aggregate Risk Assessment ................................ 21

3.5.2 Residential and Dietary Aggregate Exposure and Risk Assessment ........................ 21

3.6 Cumulative Assessment ............................................................................................ 22

3.7 Incident Reports ........................................................................................................ 22

4.0 Environmental Assessment ............................................................................................... 23

4.1 Fate and Behaviour in the Environment ................................................................... 23

4.2 Environmental Risk Characterization ....................................................................... 23

4.2.1 Risks to Terrestrial Organisms .................................................................................. 23

4.2.2 Risks to Aquatic Organisms ...................................................................................... 24

4.2.3 Environmental Incident Reports ............................................................................... 24

5.0 Value Assessment ............................................................................................................. 24

6.0 Pest Control Product Policy Considerations ..................................................................... 25

6.1 Assessment of the Active Ingredient under the Toxic Substances Management

Policy ........................................................................................................................ 25

6.2 Formulants and Contaminants of Health or Environmental Concern ...................... 25

7.0 Conclusion of Science Evaluation .................................................................................... 26

List of Abbreviations .................................................................................................................... 27

Appendix I Lists of Pyriproxyfen Products and Uses .............................................................. 29

Proposed Re-evaluation Decision – PRVD2019-10

Table 1 Registered Pyriproxyfen Products in Canada as of 1 May 2019 excluding

discontinued products or products with a submission for discontinuation ............... 29

Table 2 Registered Commercial and Restricted Class Uses of Pyriproxyfen as of 1 May 2019

excluding discontinued products or products with a submission for

discontinuation.......................................................................................................... 32

Table 3 Registered Domestic Class Uses of Pyriproxyfen as of 1 May 2019, excluding

discontinued products or products with a submission for discontinuation1 ............. 33

Appendix II Toxicological Information for Health Risk Assessment ....................................... 38

Table 1 Chemical Names of Pyriproxyfen and Select Metabolites ....................................... 38

Table 2 Summary of Toxicology Studies for Pyriproxyfen ................................................... 38

Table 3 Reference Values for Use in Human Health Risk Assessment for Pyriproxyfen ..... 50

Appendix III Dietary Exposure and Risk Assessments .......................................................... 52

Food Residue Chemistry Summary .............................................................................................. 53

Appendix IV Occupational Mixer/Loader/Applicator and Postapplication Risk Assessment 54

Table 1 Occupational Mixer/Loader/Applicator Exposure and Risk Assessment ................ 54

Table 2 Occupational Postapplication Exposure and Risk Assessment ................................ 54

Appendix V Residential Applicator and Postapplication Risk Assessment .............................. 56

Table 1 Residential Applicator Exposure and Risk Assessment ........................................... 56

Table 2 Residential Postapplication Dermal Exposure and Risk Assessment ...................... 56

Table 3 Residential Postapplication Incidental Oral Exposure and Risk Assessment for

Children (1<2 Years old) .......................................................................................... 58

Appendix VI Aggregate Risk Assessment .............................................................................. 59

Table 1 Aggregate Exposure and Risk Assessment ............................................................... 59

Appendix VII Label Amendments for Products Containing Pyriproxyfen .............................. 60

References ..................................................................................................................................... 65

Proposed Re-evaluation Decision - PRVD2019-10

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Proposed Re-evaluation Decision

Under the authority of the Pest Control Products Act, all registered pesticides must be regularly

re-evaluated by Health Canada’s Pest Management Regulatory Agency (PMRA) to ensure that

they continue to meet current health and environmental standards and continue to have value.

The re-evaluation considers data and information from pesticide manufacturers, published

scientific reports, and other regulatory agencies. Health Canada applies internationally accepted

risk assessment methods as well as current risk management approaches and policies.

Pyriproxyfen is an insect growth regulator that contributes to the management of white flies in

greenhouse vegetable and ornamental production, flea control in indoor, non-food areas of

structures and management of fleas on cats and dogs. Commercial products are formulated as

solutions, and are applied by ground application equipment by greenhouse workers and

professional applicators. Domestic-class indoor products are applied to indoor environments as a

trigger pump sprayer or pressurized product. Domestic-class pet treatment products are applied to

dogs as a shampoo, or to dogs and cats as a spot-on treatment. Currently registered products

containing pyriproxyfen can be found in the Pesticide Label Search and in Appendix I.

This document presents the proposed regulatory decision for the re-evaluation of pyriproxyfen

including the proposed risk mitigation measures to further protect human health and the

environment, as well as the science evaluation on which the proposed decision was based. All

products containing pyriproxyfen registered in Canada are subject to this proposed re-evaluation

decision. This document is subject to a 90-day public consultation period, during which the

public including the pesticide manufacturers and stakeholders may submit written comments and

additional information to the PMRA. The final re-evaluation decision will be published taking

into consideration the comments and information received.

Outcome of Science Evaluation

Pyriproxyfen contributes to the management of white flies in greenhouse vegetable and

ornamental production, flea control in indoor, non-food areas of structures and management of

fleas on cats and dogs.

With respect to human health, dietary, residential and aggregate risks from the use of

pyriproxyfen and associated end-use products have been shown to be acceptable. Occupational

risks have been shown to be acceptable with label statements updated to standard baseline

personal protective equipment. For indoor uses to control fleas and ticks, label amendments are

proposed to standardize precautionary statements, to add best practice statements as per

Regulatory Proposal PRO2018-04, Structural Pest Control Products: Label Updates and to

clarify label directions to reflect actual use conditions.

When used according to the proposed label directions, potential risks to the environment from

the use of pyriproxyfen and associated end-use products have been shown to be acceptable.

Proposed Re-evaluation Decision - PRVD2019-10

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Proposed Regulatory Decision for Pyriproxyfen

An evaluation of available scientific information found that all uses of pyriproxyfen products

meet current standards for protection of human health and the environment when used according

to proposed label directions. Under the authority of the Pest Control Products Act, Health

Canada is proposing that products containing pyriproxyfen are acceptable for continued

registration in Canada.

Registered pesticide product labels include specific directions for use. Directions include risk

mitigation measures to protect human health and the environment and must be followed by law.

No products or uses are proposed for cancellation. The proposed label amendments are

summarized below. Refer to Appendix VII for details.

Human Health

• To protect mixer/loaders and applicators, updated label statements for personal protective

equipment are proposed.

• Label statements are also proposed to address the following:

o Preventing recycled greenhouse water from being applied to outdoor food crops

o Prevent contamination of food and food surfaces during indoor applications

o Clarifying and/or ensuring consistency regarding use directions and precautionary

statements.

o Adding best practice label statements as per PRO2018-04, Structural Pest Control

Products: Label Updates

• Due to lack of data to assess occupational exposure, label statements prohibiting

application using handheld mist blower or handheld fogging equipment are proposed.

Environment

• Standard label statements to inform users of the potential toxic effects of pyriproxyfen to

aquatic organisms are proposed.

International Context

Pyriproxyfen is currently acceptable for use in other Organisation for Economic Co-operation

and Development (OECD) member countries, including the United States, the European Union,

and Australia.

As of 11 March 2019, no decision by an OECD member country to prohibit all uses of

pyriproxyfen for health or environmental reasons has been identified.

Proposed Re-evaluation Decision - PRVD2019-10

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Next Steps

The public including the registrants and stakeholders are encouraged to submit comments during

the 90-day public consultation period1 upon publication of this proposed re-evaluation decision.

All comments received during the 90-day public consultation period will be taken into

consideration in preparation of re-evaluation decision document,2 which could result in revised

risk mitigation measures. The re-evaluation decision document will include the final re-

evaluation decision, the reasons for it and a summary of comments received on the proposed re-

evaluation decision with Health Canada’s responses.

Additional Scientific Information

No additional information is required at this time.

1 “Consultation statement” as required by subsection 28(2) of the Pest Control Products Act.

2 “Decision statement” as required by subsection 28(5) of the Pest Control Products Act.

Proposed Re-evaluation Decision - PRVD2019-10

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Science Evaluation

1.0 Introduction

2.0 Technical Grade Active Ingredient

2.1 Identity

Common name

Pyriproxyfen

Function

Insect Growth Regulator

Chemical Family

pyridine-based pesticide

Chemical name

International Union of Pure

and Applied Chemistry

(IUPAC)

rac-2-{[(2R)-1-(4-phenoxyphenoxy)propan-2-

yl]oxy}pyridine

Chemical Abstracts Service

(CAS)

2-[1-methyl-2-(4-

phenoxyphenoxy)ethoxy]pyridine

CAS Registry Number

95737-68-1

Molecular Formula

C20H19NO3

Structural Formula

NOO

Molecular Weight

321.37 g/mol

Purity of the Technical Grade Active

Ingredient

98.7%

Registration Number

25105

2.2 Physical and Chemical Properties

Property

Result

Vapour pressure at 25°C

< 0.013 mPa

Ultraviolet (UV) / visible spectrum

max

~ 270 nm (pH 3-11)

λmax 278 nm (pH 1)

Solubility in water at 25°C

0.367 mg/L

Proposed Re-evaluation Decision - PRVD2019-10

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Property

Result

n-Octanol/water partition coefficient

Log Kow = 5.37

Dissociation constant

~ 3.62 (calculated)

2.3 Description of Registered Pyriproxyfen Uses

In Appendix I, Table 1 lists all pyriproxyfen products that are registered under the authority of

the Pest Control Products Act. In Appendix I, Table 2 lists all Commercial Class uses for which

pyriproxyfen is presently registered, while in Appendix I, Table 3 lists all Domestic Class uses

for which pyriproxyfen is presently registered.

All uses were supported by the registrant at the time of re-evaluation initiation and were therefore

considered in the health and environmental risk assessments of pyriproxyfen.

3.0 Human Health Assessment

3.1 Toxicology Summary

Pyriproxyfen is a pyridine insecticide that is an analogue of insect juvenile hormone. A detailed

review of the toxicological database for pyriproxyfen was conducted. The database is complete,

consisting of the full array of toxicity studies currently required for hazard assessment purposes.

Most of the studies were carried out in accordance with currently accepted international testing

protocols and Good Laboratory Practices. The scientific quality of the data is high and the

database is considered adequate to characterize the potential health hazards associated with

pyriproxyfen.

Toxicokinetic investigations were conducted in rats following gavage administration of phenyl-

or pyridyl-radiolabelled pyriproxyfen. Administration of a single low dose of pyriproxyfen

resulted in rapid but low absorption. Males showed higher peak concentrations in blood than

females in the first 24 hours after administration. Maximum tissue concentrations were observed

at eight hours post-dosing with highest concentrations in the liver, blood, kidneys and adipose

tissue. In rats receiving single low, single high or repeated low doses, the highest tissue

concentrations at seven days post-dosing were observed in adipose tissue with other tissues

showing negligible amounts. Pyriproxyfen was extensively and rapidly eliminated in the feces of

rats within 48 hours. Minor amounts of the administered radioactivity were eliminated in urine,

with negligible amounts in expired air. There were no differences in tissue distribution or

elimination attributable to sex, dose level, dosing regimen or position of radiolabel. Fecal

metabolites consisted primarily of 4'-OH-pyr with lesser amounts of unchanged pyriproxyfen.

Minor fecal metabolites included 5"4'-OH-pyr and, depending on the position of the radiolabel,

POPA, 2'-OH-pyr, 5"-OH-pyr, DPH-pyr and sulfate and glucuronide conjugates of some of the

identified metabolites. Unchanged pyriproxyfen and 4'-OH-pyr were either absent, or seen in

minor amounts in the urine of treated rats. Other urinary metabolites, all representing less than

5% of the administered dose, included PYPAC and sulfate conjugates. Chemical names of the

metabolites that were further characterized can be found in Appendix II, Table 1.

Proposed Re-evaluation Decision - PRVD2019-10

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The major pathway of pyriproxyfen metabolism in rats involves hydroxylation at the 4'-position

of the terminal phenyl ring. Minor pathways include hydroxylation at the 2'-position of the

terminal phenyl ring and at the 5"-pyridyl position, dephenylation, cleavage of ether linkages, and

formation of glucuronide and sulfate conjugates. There were no significant effects of sex or dose

on the metabolic pattern of pyriproxyfen in rats. With repeated dosing, the amount of metabolite

produced by oxidation at the 4' position was significantly greater in females as compared to

males.

Pyriproxyfen was of low acute toxicity in rats when administered via the oral and dermal routes

of exposure and of slight acute toxicity via the inhalation route. Clinical signs of toxicity

following acute oral exposure included diarrhea, soft feces and reduced spontaneous activity.

Transient clinical signs following acute inhalation exposure included salivation and urinary

incontinence. Pyriproxyfen was minimally irritating to the eyes and non-irritating to the skin of

rabbits, and was not a dermal sensitizer in guinea pigs in the Maximization assay.

The liver was identified as a target organ throughout the database. In short-term dietary or

capsule administration studies, increased liver weights were seen in rats, mice and dogs;

cytoplasmic changes and increased cholesterol and phospholipids were also noted in rats and

dogs. At high dose levels, dogs also exhibited increased serum enzyme levels, increased

triglycerides, centriacinar fibrosis and bile duct hyperplasia. The kidney was also a target of

toxicity with increased weights in rats and dogs and tubular nephrosis with dilation of the renal

tubules and focal mineralization in mice. The hematological system was affected in the rodent

short-term dietary studies, as demonstrated by decreased red blood cell, hematocrit and

hemoglobin counts. Decreased bodyweight was often concomitant with the observed effects on

the liver, kidney or hematological system.

No treatment-related effects were noted in a short-term dermal toxicity study in rats at the limit

dose of testing (1000 mg/kg bw/day). A NOAEC of 0.48 mg/L was established for rats exposed

via inhalation for four weeks based on transient salivation, decreased bodyweights and absolute

lung weights in males at the limit dose concentration of 1 mg/L.

In a dietary chronic toxicity study in rats, effects included reductions in bodyweight, increases in

liver weight, and transient increases in cholesterol, phospholipids and urinary protein. In a dietary

oncogenicity study in mice, survival was reduced in males, resulting in a study NOAEL of 16

mg/kg bw/day. The primary cause of death was identified as amyloidosis. Although the overall

incidence of amyloidosis in decedents was unaffected by treatment, males that died showed an

increased severity of amyloidosis, particularly of the kidney, thyroid, parathyroid and stomach.

Males and females at a higher dose level showed effects on kidneys (increased incidences of

chronic progressive nephropathy, mineralized tubules), liver (increased weight), and blood

(decreased red blood cells, hemoglobin and hematocrit) as well as decreased bodyweight and

accelerated development and severity of amyloidosis. Reduced survival in females occurred at

this dose level. No treatment-related increase in tumour incidences was evident in either the rat

or mouse studies.

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Pyriproxyfen was negative in a battery of genotoxicity assays including a bacterial reverse

mutation assay, several in vitro assays (mammalian gene mutation assay, unscheduled DNA

synthesis assay and chromosome aberration assay) and an in vivo micronucleus assay.

In the dietary two-generation reproductive toxicity study in rats, there was no evidence of

sensitivity of the young. Increased liver and kidney weights were recorded in F1 males which

progressed to pathological changes at the highest dose level. Decreases in bodyweight during the

pre-mating phase were apparent at the latter level in both generations. Pup bodyweights were

reduced at the highest dose level tested in both generations. There was no effect on reproductive

parameters in the study.

Three gavage developmental toxicity studies in rats were available, assessing different windows

of exposure, namely pre-implantation, during organogenesis, and post-organogenesis through

lactation. No evidence of sensitivity of the young was apparent in these studies. Maternal toxicity

occurred at the same dose level in all three studies and consisted of decreased bodyweight and

food consumption and increased liver and kidney weights. At higher dose levels, mortality was

noted in pregnant dams after several doses during organogenesis or post-organogenesis. No

adverse effects on fetal development were noted at the limit dose in the non-guideline pre-

implantation exposure study; however, a slight decrease in the number of corpora lutea was seen

in the dams at this level. In the study with exposure during organogenesis, an increased incidence

of a variation (opening of the seventh cervical vertebra foramen transversium) was noted in

fetuses. In this study, a subgroup of dams was allowed to deliver their young. Findings in these

offspring at the highest dose level tested included an increased incidence of renal pelvic

dilatation in three and eight-week-old pups and increased kidney weights in eight-week-old pups.

No effects were evident on the sensory function, behavior, motor co-ordination, learning ability

or reproductive performance in pups from this study. In the non-guideline study with

pyrifproxyfen exposure occurring post-organogenesis through lactation, the offspring NOAEL of

100 mg/kg bw/day was based on reduced pup weights at birth and throughout lactation and an

increased incidence of dilatation of the renal pelvis in three-week-old pups. A decrease in pup

viability at postnatal day (PND) 21 was also observed, which was deemed equivocal at this dose

level due to the magnitude of the response. At a higher dose level, pup viability was clearly

affected at birth and throughout the lactation period, reflected in reduced mean litter size. A

slight delay in vaginal opening was also noted in pups at the high-dose level. Increased pre-

implantation loss was observed in high-dose pups that were assessed during adulthood for

reproductive performance, but sensory function, behavior, motor coordination and learning

ability were unaffected by treatment. Overall, the data suggest that the most sensitive window of

exposure was post-organogenesis through lactation; the potential mobilization of pyriproxyfen fat

stores during lactation could play a role in this sensitivity.

In a gavage rabbit developmental toxicity study, maternal toxicity was evident based on the

occurrence of abortions or premature deliveries as well as decreased weight gain with a resultant

NOAEL of 100 mg/kg bw/day. Although the abortions/premature deliveries co-occurred with a

reduction or absence of food intake in the affected dose, it was unknown if this was a causal

factor or merely a correlation with the occurrence of the abortions/premature deliveries.

Proposed Re-evaluation Decision - PRVD2019-10

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At the highest dose level tested (limit dose), additional effects in maternal animals included

weight loss and mortality. Fetal effects were limited to an increased incidence of a variation

(abnormal location of posterior vena cava) at the highest dose level.

There was no evidence of selective neurotoxicity in either the acute gavage or 90-day dietary

neurotoxicity studies in the rat. Effects in the acute neurotoxicity study were limited to a transient

reduction in motor activity on the day of dosing in male animals at a high dose level. Reduced

bodyweight and food consumption were the only effects observed in the 90-day neurotoxicity

study.

No adverse effects were noted in a 28-day dietary immunotoxicity study in mice. A dietary range-

finding study conducted in mice with higher dose levels showed effects on bodyweight as well as

liver and kidney toxicity. Overall, there was no evidence of immune dysregulation.

A battery of endocrine-related studies was conducted for the United States Endocrine Disruptor

Screening Program. In in vitro assays, pyriproxyfen was negative for estrogen and androgen

receptor binding and aromatase inhibition and did not affect testosterone production, but was a

weak inducer of estradiol production in the steroidogenesis assay. Pyriproxyfen did not show

endocrine-related toxicity in either the uterotrophic or Hershberger assays conducted via gavage

in rats. In the female pubertal assay, rats gavage-dosed with pyriproxyfen showed a slight delay

for incomplete vaginal opening and a reduction in females cycling regularly at the limit dose

level concurrent with evidence of hepatic and renal toxicity; the time for complete vaginal

opening was unaffected by treatment. Minimal evidence of thyroid toxicity was present in this

study. In the male pubertal assay, rats gavage-dosed with pyriproxyfen showed decreases in

serum testosterone levels and in the weights of androgen sensitive organs as well as a slight delay

for complete preputial separation. These effects occurred in the presence of hepatic and renal

toxicity. Slight changes in thyroid pathology were also evident in this study but thyroid hormones

were unaffected by treatment. Androgen-related effects (decreased testosterone as well as

weights of androgen-sensitive organs, delayed preputial separation) were also observed in a

mechanistic study in gavage-dosed pubertal male rats. In addition to the co-occurring indicators

of hepatic and renal toxicity in this study (organ weight changes, clinical chemistry alterations

and histopathology), liver enzyme induction was evident. No effect on 17β-hydroxysteroid

dehydrogenase activity in the testis was evident. The data suggest that the potential anti-

androgenic effects could be secondary to the increased metabolism of testosterone by the liver.

Concern was raised in the public domain regarding the relationship between pyriproxyfen and the

increase in microcephaly cases in Brazil in 2015 and 2016. Pyriproxyfen was added to the

drinking water supply to combat the larva of mosquitos that carried the Zika virus. Although the

increase in microcephaly has been strongly correlated with the mosquito-borne Zika virus, one

publication considered a possible link with pyriproxyfen exposure (PMRA #2857241). The

authors speculated that pyriproxyfen has cross-reactivity with retinoic acid, a known

developmental toxicant, but did not provide data to support this claim. The authors cited a

decrease in relative brain weight seen in eight-week-old male pups from dams that received

300 mg/kg bw/day in the rat developmental toxicity study (PMRA #1143907) as supporting

evidence for their concern. This observation was not considered treatment-related by the PMRA

for several reasons including: lack of a dose relationship, lack of a similar response in female

Proposed Re-evaluation Decision - PRVD2019-10

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pups, the lack of an effect on absolute brain weight (considered to be a better measure of

response due to the conserved nature of brain weight) and the lack of a similar observation in the

reproductive toxicity assay.

Results of a published case-control study (PMRA #2857240) did not identify an association

between microcephaly and pyriproxyfen; however, there was a strong association between

microcephaly and the Zika virus. In a published ecological study (PMRA #2857242), there was

no difference in the prevalence of microcephaly between Brazilian municipalities using

pyriproxyfen and those using Bacillus thuringiensis israelensis. Although these epidemiological

studies had limitations, the findings did not support a concern for pyriproxyfen. Results of an

additional published study (PMRA #2857243) did not reveal evidence of brain malformations or

significant changes in the number of stem cells in the developing central nervous system in

zebrafish embryos. The findings in these studies, taken together with the absence of treatment-

related malformations in the developmental and reproductive toxicity studies, do not suggest that

pyriproxyfen was a causal factor in the increase in microcephaly cases in Brazil.

Further data in the scientific literature included two in vitro studies that indicated weak

estrogenic activity, and two in vitro studies that demonstrated cytotoxicity. The findings in these

studies did not substantially impact the current understanding of pyriproxyfen toxicity.

The mammalian metabolites 4'-OH-pyr, 5"-OH-pyr, DPH-pyr, POPA and PYPAC were of low

acute oral toxicity in the mouse and negative in a bacterial reverse mutation assay. Slight acute

oral toxicity in mice and negative findings in a bacterial reverse mutation assay were noted for

2,5-OH-py, a minor metabolite noted in the lactating goat metabolism study. A plant metabolite,

2-OH-py, was of high acute toxicity in the mouse; however, it was considered a minor

metabolite. It was also negative in a bacterial reverse mutation assay.

Results of the toxicology studies conducted on laboratory animals with pyriproxyfen are

summarized in Appendix II, Table 2. The toxicology reference values for use in the human health

risk assessment are summarized in Appendix II, Table 3.

3.1.1 Pest Control Products Act Hazard Characterization

For assessing risks from potential residues in food or from products used in or around homes or

schools, the Pest Control Products Act requires the application of an additional 10-fold factor to

threshold effects to take into account completeness of the data with respect to the exposure of,

and toxicity to, infants and children, and potential prenatal and postnatal toxicity. A different

factor may be determined to be appropriate on the basis of reliable scientific data.

With respect to the completeness of the toxicity database as it pertains to the toxicity to infants

and children, the database contains the full complement of required studies including gavage

developmental toxicity studies in rats and rabbits and a dietary two-generation reproductive

toxicity study in rats. Additional data on the young were available from gavage pubertal assays

conducted in juvenile rats with pyriproxyfen.

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With respect to potential prenatal and postnatal toxicity, there was no indication of increased

sensitivity of fetuses or offspring compared to parental animals in the reproductive and

developmental toxicity studies. Minor developmental effects (increased incidence of fetal

variations) were observed in the rat and rabbit guideline developmental toxicity studies; however,

these effects occurred in the presence of maternal toxicity. A serious effect, abortion/premature

delivery, was noted in maternal animals in the rabbit developmental toxicity study. Each of the

affected animals ceased consuming food and lost weight for several days prior to litter loss. It

was unknown whether the abortions/premature deliveries were the consequence of a direct effect

on the fetus or secondary to overt toxicity in the maternal animal. A reduction in the number of

corpora lutea was noted in rats administered pyriproxyfen prior to the implantation period in a

non-guideline developmental toxicity study; however, this effect was only noted at the limit dose

of testing and in the presence of significant maternal toxicity including mortality. In a non-

guideline developmental toxicity study in rats in which dams were dosed post-organogenesis

through lactation, pups at the mid-dose level exhibited renal effects, decreased weight at birth

and throughout lactation, and an equivocal decrease in viability at PND 21. The equivocal

decrease in viability at this dose level was deemed a low concern due to the small magnitude of

the effect. At a higher dose level, pup effects included clearly reduced viability at birth and

throughout lactation, delayed sexual development and an increase in pre-implantation loss when

these pups were mated at adulthood. In the rat reproductive toxicity study, pup weight was

reduced in both generations at a dose level that resulted in parental toxicity (effects on liver,

kidney and bodyweight). Delayed sexual development was noted in young male and female rats

in the pubertal assays but occurred concurrently with other systemic toxicity (liver, kidney and

bodyweight effects).

Overall, endpoints in the young were well-characterized and there was no evidence of sensitivity.

Endpoints considered serious in nature included the abortions/premature deliveries in rabbits, the

decrease in corpora lutea in rats and the clear effects on rat pup viability. On the basis of this

information, the Pest Control Products Act factor (PCPA factor) was reduced to threefold when

these endpoints were used as the point of departure for risk assessment. In scenarios where other

endpoints were selected, the risk assessment was protective of the serious endpoints and the

PCPA factor was reduced to onefold.

3.2 Dietary Exposure and Risk Assessment

In a dietary exposure assessment, the PMRA determines how much of a pesticide residue,

including residues in meat and milk, may be ingested with the daily diet. Exposure to

pyriproxyfen from potentially treated imported foods is also included in the assessment. Dietary

exposure assessments are age-specific and incorporate the different eating habits of the

population at various stages of life (infants, children, adolescents, adults and seniors). For

example, the assessments take into account differences in children’s eating patterns, such as food

preferences and the greater consumption of food relative to their body weight when compared to

adults. Dietary risk is then determined by the combination of the exposure and the toxicity

assessments. High toxicity may not indicate high risk if the exposure is low. Similarly, there may

be risk from a pesticide with low toxicity if the exposure is high.

Proposed Re-evaluation Decision - PRVD2019-10

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The PMRA considers limiting use of a pesticide when exposure exceeds 100% of the reference

dose. The PMRA’s Science Policy Note SPN2003-03, Assessing Exposure from Pesticides, A

User’s Guide, presents detailed risk assessment procedures.

Residue estimates used in the dietary risk assessment may be based conservatively (in other

words, are high-end estimates) on the maximum residue limits (MRLs) or the field trial data

representing the residues that may remain on food after treatment at the maximum label rate.

Surveillance data representative of the national food supply may also be used to derive a more

accurate estimate of residues that may remain on food when it is purchased. These include the

Canadian Food Inspection Agency’s (CFIA) National Chemical Residue Monitoring Program

and the United States Department of Agriculture Pesticide Data Program (USDA PDP). Specific

and empirical processing factors as well as specific information regarding percent of crops

treated may also be incorporated to the greatest extent possible.

Sufficient information was available to adequately assess the dietary exposure and risk from

pyriproxyfen. The chronic dietary exposure and risk assessments were conducted using the

Dietary Exposure Evaluation Model - Food Commodity Intake Database™ (DEEM-FCID™,

Version 4.02, 05-10-c) program which incorporates consumption data from the National Health

and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA) for the years

2005-2010 available through the Centers for Disease Control and Prevention’s (CDC) National

Center for Health Statistics (NCHS). Further details on the consumption data are available in

Science Policy Note SPN2014-01, General Exposure Factor Inputs for Dietary, Occupational

and Residential Exposure Assessments.

3.2.1 Determination of Acute Reference Dose

An acute reference dose (ARfD) was not required as no endpoint of concern attributable to a

single exposure was identified.

3.2.2 Acute Dietary Exposure and Risk Assessment

An acute dietary exposure and risk assessment was not required.

3.2.3 Determination of Acceptable Daily Intake

To estimate risk from repeated dietary exposure, the mouse oncogenicity study with a NOAEL of

16 mg/kg bw/day was selected. At the LOAEL of 79 mg/kg bw/day, reduced survival and

increased severity of amyloidosis were observed. This study provides the lowest NOAEL in the

database. Standard uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for

intraspecies variability were applied. As discussed in the Pest Control Products Act Hazard

Characterization Section, the PCPA factor was reduced to onefold. The composite assessment

factor (CAF) is thus 100.

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The acceptable daily intake (ADI) is calculated according to the following formula:

ADI = NOAEL = 16 mg/kg bw/day = 0.2 mg/kg bw/day of pyriproxyfen

CAF 100

The ADI provides a margin of 500 or greater to the NOAELs for abortions/premature deliveries

in rabbits and reduced corpora lutea and pup viability in rats.

3.2.4 Chronic Dietary Exposure and Risk Assessment

Generally, the chronic dietary risk is calculated using average consumption of different foods and

the average residue values on those foods. For pyriproxyfen specifically, the average

consumption values were used and the maximum potential residues as noted below were used.

This would result in conservative (high-end) estimates of exposure. The estimated exposure was

then compared to the ADI, which is an estimate of the level of daily exposure to a pesticide

residue that, over a lifetime, is believed to have no significant harmful effects. When the

estimated exposure is less than the ADI, the chronic dietary exposure is shown to be acceptable.

The exposure assessment was conducted using the Canadian maximum residue limits (MRLs) or

American tolerances for pyriproxyfen (whichever was greater). Available CODEX MRLs were

used for commodities without Canadian MRLs or American tolerances. For agricultural crops,

100% crop treated was assumed. Available experimental processing factors were also used in the

assessment.

In the United States, a tolerance of 0.1 ppm pyriproxyfen has been established for all

commodities not listed as having specific American tolerances. This tolerance is intended for

residues on foods resulting from the use of pyriproxyfen products in food handling

establishments. Use of pyriproxyfen in food handling establishments is not a registered use in

Canada. However, in consideration of potential food imports to Canada from the United States,

the American tolerance of 0.1 ppm was used in the dietary exposure assessment for all

commodities for which no MRL or tolerance has been established. For these commodities, 4.65%

were considered to be treated based on percent of food handling establishments treated in the

United States. In addition, commodities with existing Canadian MRLs lower than 0.1 ppm were

assigned the 0.1 ppm for the dietary assessment, since as noted above, the highest value of either

the Canadian MRL or American tolerance was used in the assessment.

CFIA and USDA PDP residue monitoring data for pyriproxyfen were available but were not used

in this assessment; there was no need for this level of residue refinement at this time. The

monitoring data showed non-detect values for the majority of commodities, with only a few

detected residues but at levels lower than the established MRLs or tolerances.

The chronic dietary risk assessment was conducted for the general population and all population

subgroups. The chronic dietary exposure for the general population was approximately 5% of the

ADI. Chronic exposures for population subgroups ranged from approximately 4% of the ADI to

13% of the ADI. Children 1–2 years old were the subpopulation expected to be subject to the

highest exposures relative to bodyweight. Pyriproxyfen dietary risk was, therefore, shown to be

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acceptable for the general population and all population subgroups. For more information on the

dietary risk estimates or the residue chemistry information used in the dietary assessment, see

Appendix III.

Best practice label statements are proposed to clarify label directions as it relates to potential

residues on food as follows:

• As there are no field uses of pyriproxyfen, label statements to prevent recycled

greenhouse water from being applied to outdoor food crops;

• Label statements to prevent contamination of food and food surfaces during indoor

applications for control of fleas and ticks.

See Appendix VII for specific label statements.

3.2.5 Cancer Assessment

There was no evidence of carcinogenicity and therefore, a cancer risk assessment was not

necessary.

3.3 Exposure from Drinking Water

Given that pyriproxyfen is registered for greenhouse and indoor uses only, exposure of drinking

water sources was deemed minimal and, therefore, drinking water contribution to the dietary

exposure was not considered in this assessment. Label statements are being proposed to prevent

residues from entering drinking water sources. See Appendix VII for specific label statements.

3.4 Occupational and Non-Occupational Exposure and Risk Assessment

Occupational and residential risk is estimated by comparing potential exposures with the most

relevant endpoint from toxicology studies to calculate a margin of exposure (MOE). This is

compared to a target MOE incorporating uncertainty factors protective of the most sensitive

subpopulation. If the calculated MOE is less than the target MOE, it does not necessarily mean

that exposure will result in adverse effects, but mitigation measures to reduce risk would be

required.

3.4.1 Toxicology Reference Values

Short- and Intermediate-Term Dermal and Inhalation

For short- and intermediate-term dermal and inhalation risk assessment for adults, the oral

developmental toxicity study in rabbits was selected. A NOAEL of 100 mg/kg bw/day was

established. At 300 mg/kg bw/day, an increase in abortions/premature deliveries was observed in

the presence of maternal toxicity. Although short-term dermal and inhalation toxicity studies

were available, they were not chosen for reference value selection since the design of those

studies does not allow for the assessment of the relevant endpoint of concern. Standard

uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies

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variability were applied. For residential scenarios, as discussed in the Pest Control Products Act

Hazard Characterization Section, the PCPA factor was reduced to threefold, resulting in a target

margin of exposure (MOE) of 300. For occupational scenarios, the target MOE was also 300

reflecting the use of an additional threefold factor for a serious effect in the presence of maternal

toxicity.

For short and intermediate-term dermal and inhalation risk assessment for children, the oral

developmental toxicity study in rats that included a postnatal phase was selected. A NOAEL of

100 mg/kg bw/day was established. At 300 mg/kg bw/day, pup weight was reduced along with an

equivocal reduction in pup viability. Although short-term dermal and inhalation toxicity studies

were available, they were not chosen for reference value selection since the design of those

studies does not allow for the assessment of the relevant endpoint of concern. A target MOE of

100 was established based on standard uncertainty factors of 10-fold for interspecies

extrapolation and 10-fold for intraspecies variability, along with a PCPA factor of onefold, as

discussed in the Pest Control Products Act Hazard Characterization Section.

Long-term Dermal and Inhalation

For long-term dermal and inhalation risk assessment, the mouse oncogenicity study with a

NOAEL of 16 mg/kg bw/day was selected. At the LOAEL of 79 mg/kg bw/day, reduced survival

and increased severity of amyloidosis were observed. Standard uncertainty factors of 10-fold for

interspecies extrapolation and 10-fold for intraspecies variability were applied resulting in a

target MOE of 100. For residential scenarios, the PCPA factor was reduced to onefold as

discussed in the Pest Control Products Act Hazard Characterization Section.

Non-Dietary Oral Ingestion (Children, Short-term)

For non-dietary oral ingestion, the 90-day oral toxicity study in rats with a NOAEL of 24 mg/kg

bw/day in rats was selected for risk assessment. At the LOAEL of 118 mg/kg bw/day, effects

were noted on the liver and hematological system. Standard uncertainty factors of 10-fold for

interspecies extrapolation and 10-fold for intraspecies variability, along with a PCPA factor of

onefold, as discussed in the Pest Control Products Act Hazard Characterization Section, resulted

in a target MOE of 100.

Dermal Absorption

No chemical-specific dermal absorption studies were submitted to the PMRA. Therefore, dermal

absorption of 100% was used in the risk assessment.

3.4.2 Residential Exposure and Risk Assessment

Residential risk assessment involves estimating risks to the general population, including

children, during or after pesticide application.

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The USEPA has generated standard default assumptions for developing residential exposure

assessments for both applicator and postapplication exposures when chemical- and/or site-

specific field data are limited. These assumptions may be used in the absence of, or as a

supplement to, chemical- and/or site-specific data and generally result in high-end estimates of

exposure. These assumptions are outlined in the Standard Operating Procedures (SOP) for

Residential Pesticide Exposure Assessments (USEPA, 2012).

The following sections from the USEPA Residential SOPs were used to assess residential

exposure to pyriproxyfen:

• Section 7: Indoor Environments

• Section 8: Treated Pets

3.4.2.1 Residential Applicator Exposure and Risk Assessment

Residential applicators are adults who apply domestic-class pyriproxyfen products that are

registered for use inside the home. Applicators are assumed to be adults (>16 years old) and to

wear shorts, short-sleeved shirts, shoes and socks.

There is potential exposure to residential applicators applying pyriproxyfen inside homes and to

pets (dogs and cats). Based on typical use patterns, the representative scenarios identified were:

• Applying pressurized product formulations to indoor environments

• Applying liquid formulations using ready-to-use trigger pump sprayers to indoor

environments

• Applying liquid formulations as a shampoo to dogs

• Applying liquid formulations using a ready-to-use spot-on application to dogs and cats

Residential applicators have the potential for short-to-intermediate term exposure (<6 months)

due to seasonality of the pests listed on the label (for example, fleas, ticks and mosquitoes).

Route-specific MOEs for residential applicators are outlined in Appendix V, Table 1. Calculated

MOEs for dermal, inhalation, and combined (dermal + inhalation) exposures for residential

applicators of pyriproxyfen exceeded target MOEs for all scenarios, and therefore, risks were

shown to be acceptable.

3.4.2.2 Residential Postapplication Exposure and Risk Assessment

Residential postapplication exposure refers to an exposure scenario in which an individual is

exposed through dermal, inhalation, and/or incidental oral (non-dietary ingestion) routes as a

result of being in a residential environment or contacting a surface that has been previously

treated with a pesticide. The surface could have been treated by a residential applicator using a

domestic-class product or a commercial applicator hired to treat the residential area.

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There is potential for intermittent, short- to intermediate-term exposure to adults and children

through contact with transferable residues following application of pyriproxyfen to indoor

environments and to pets. Adults and children have the potential for postapplication dermal

exposure; children aged 1 to <2 years old also have the potential for incidental oral exposure.

Since children aged 1 to 2 years have the greatest potential for exposure, risk outcomes for this

population of children are presented. Inhalation exposure is considered to be minimal compared

to dermal exposure, since pyriproxyfen has a low vapour pressure and meets the criteria for an

inhalation waiver based on low volatility. Thus, a residential postapplication inhalation exposure

assessment was not required.

The following scenarios were assessed for residential use of products containing pyriproxyfen:

• Indoor Environments:

o Adults and children (1 to <2 years old) dermal exposure resulting from activities

indoors.

o Incidental oral (hand-to-mouth, object-to-mouth) exposure to children (1 to <2

years old) in indoor environments.

• Treated Pets:

o Adults and children (1 to <2 years old) dermal exposure resulting from activities

with treated pets.

o Incidental oral (hand-to-mouth) exposure to children (1 to <2 years old) from

treated pets.

The highest application rate was used in the postapplication risk assessment for pyriproxyfen. It

is assumed that individuals contact previously treated surfaces and pets on the same day the

pesticide treatment is applied. Multiple applications were not assessed for indoor and pet uses of

pyriproxyfen since exposure on the day of application (Day 0) without any dissipation was

assumed for the entire duration of exposure. These assumptions would result in conservative or

high-end estimates of exposure.

Dermal Exposure

Postapplication dermal exposure was calculated using activity-specific transfer coefficients, for

treated surfaces or treated pet fur, dislodgeable residue (residue transfer to skin) and exposure

time. A transfer coefficient is a factor that relates exposure to dislodgeable residues and the

amount of treated surface that a person contacts while performing activities in a given time

period (usually expressed in units of cm2 per hour). It is specific to a particular population and

activity/location (for example, children playing on soft surfaces such as carpets).

Calculated dermal MOEs for residential postapplication exposure to pyriproxyfen exceeded

target MOEs for all populations and scenarios, and therefore, risks are shown to be acceptable.

The residential dermal postapplication risk assessment is outlined in Appendix V, Table 2.

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Incidental Oral Exposure

Postapplication incidental oral exposure assumes that pesticide residues are transferred to the

skin of children’s (1 to <2 years old) hands while playing on treated indoor surfaces or with

treated pets, and are subsequently ingested as a result of hand-to-mouth transfer. For indoor

applications, residues that could result on children’s toys and which could subsequently be

ingested as a result of mouthing activity with the toy are also considered (object-to-mouth

transfer).

Calculated incidental oral MOEs for residential postapplication exposure to pyriproxyfen

exceeded target MOEs, and therefore, risks are shown to be acceptable. The residential incidental

oral postapplication risk assessment is outlined in Appendix V, Table 3.

3.4.2.3 Label Statements

For end-use products with directions for indoor uses to control fleas and ticks, label amendments

are proposed as follows:

• Clarifying and/or ensuring consistency regarding use directions and precautionary

statements.

• Adding best practice label statements as per PRO2018-04, Structural Pest Control

Products: Label Updates.

See Appendix VII for specific label statements for pyriproxyfen.

3.4.3 Occupational Exposure and Risk Assessment

There is potential for exposure to pyriproxyfen in occupational scenarios from workers handling

the pesticide during the application process, and potential for postapplication exposure from

workers entering into areas or handling pets previously treated with pyriproxyfen.

3.4.3.1 Mixer, Loader, and Applicator Exposure and Risk Assessment

There are potential exposures to mixers, loaders, and applicators. The following scenarios were

assessed:

• Application to greenhouse crops

• Application in indoor structures, including homes, using the commercial-class product

• Application of domestic-class spot-on or shampoo products to pets by workers

Typically, it is assumed that commercial applicators or workers would not be using domestic-

class products. However, for pyriproxyfen, since there are no commercial-class products

registered for application to pets, it was assumed that workers would be using domestic-class

products (for example, in veterinary clinics).

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Greenhouse and Indoor Structures

For greenhouse and indoor structures, the following application equipment were assessed:

• Backpack application to greenhouse ornamentals, tomatoes, cucumbers, peppers and

eggplants

• Manually-pressurized handwand application to indoor structures and greenhouse

ornamentals, tomatoes, cucumbers, peppers and eggplants

• Mechanically-pressurized handgun application to greenhouse ornamentals, tomatoes,

cucumbers, peppers and eggplants

Farmers and commercial applicators may handle pyriproxyfen for short to intermediate periods of

time depending on the crop and use site. Therefore, the short-to-intermediate endpoints were

used for all scenarios.

Exposure was estimated for baseline personal protective equipment (PPE): long pants, long-

sleeved shirt, chemical-resistant gloves, socks and shoes.

No appropriate chemical-specific handler exposure data were available for pyriproxyfen.

Therefore, dermal and inhalation exposures were estimated using data from the Pesticide

Handlers Exposure Database Version 1.1 (PHED). PHED is a compilation of generic

mixer/loader applicator passive dosimetry data with associated software that facilitates the

generation of scenario-specific exposure estimates based on formulation type, application

equipment, mix/load systems and level of PPE.

In addition, for application to indoor structures, a passive dosimetry study that monitored

exposure of pest control operators (PCOs) applying liquid products indoors as a surface spray

using a manually-pressurized handwand was used.

Data were not available to assess exposures when using handheld mist blower or handheld

fogging equipment. Therefore, label statements prohibiting application with these equipment are

proposed.

Route-specific MOEs for mixer/loaders and applicators are outlined in Appendix IV, Table 1.

Calculated MOEs from dermal, inhalation, and combined (dermal + inhalation) routes for

mixer/loaders and applicators of pyriproxyfen exceeded target MOEs for all scenarios, and

therefore, risks are shown to be acceptable.

Since the assessment was conducted with handlers wearing baseline PPE, label statements are

proposed to be added to labels currently lacking this PPE. Specifically, to protect mixer/loaders

and applicators applying in indoor environments to control fleas, baseline PPE is proposed.

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Application to Pets

There are no specific exposure data for commercial handlers (for example, veterinarians,

groomers) using domestic-class spot-on or shampoo products to treat pets. Therefore, exposure

was compared to the residential applicator in terms of amount of product handled, number of pets

treated, PPE worn, and margins of exposure. For commercial users, the extent of exposure is

uncertain; however, these workers typically wear PPE when applying pet products, such as a

laboratory coat/apron. The number of animals treated per day by a worker with spot-on or

shampoo products in animal facilities may be higher than for residential applicators treating their

own pets. However, it was assumed that applying pet products is only one of many tasks that

workers would do in a typical day, and it may not always be the same product being applied.

Risks were shown to be acceptable for residential applicators (see Section 3.4.2), and based on

the exposure considerations above, risks are expected to be acceptable for commercial users as

well.

3.4.3.2 Postapplication Worker Exposure and Risk Assessment

There is potential exposure to workers entering treated sites or handling treated pets. Possible

occupational postapplication worker scenarios include:

• Agriculture: Workers entering treated greenhouses to conduct agronomic activities

• Indoor Structures: Workers entering treated commercial, industrial or institutional

locations

• Pet Uses: Veterinarians or other workers handling treated pets.

No chemical-specific data were available to assess postapplication exposure to workers.

Agriculture

The postapplication occupational risk assessment considered exposures to workers who enter

treated sites to conduct agronomic activities involving foliar contact (for example, scouting).

Based on the use of pyriproxyfen in greenhouse crops, there is potential for long-term

postapplication exposure to pyriproxyfen residues for workers.

Potential exposure to postapplication workers was estimated using updated activity-specific

transfer coefficients (TCs), and default dislodgeable foliar residue (DFR) values, since chemical-

specific DFR data were not available (see below). The DFR refers to the amount of residue that

can be dislodged or transferred from a surface, such as leaves of a plant. The TC is a measure of

the relationship between exposure and DFRs for individuals engaged in a specific activity, and is

calculated from data generated in field exposure studies. The TCs are specific to a given crop and

activity combination, and reflect standard agricultural work clothing worn by adult workers.

Activity-specific TCs from the Agricultural Re-entry Task Force (ARTF) were used.

Postapplication exposure activities for agricultural crops include (but are not limited to):

harvesting, weeding and scouting.

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For more information about estimating worker postapplication exposure, refer to the PMRA’s

Regulatory Proposal PRO2014-02, Updated Agricultural Transfer Coefficients for Assessing

Occupational Postapplication Exposure to Pesticides.

Since no acceptable chemical-specific DFR studies were available for pyriproxyfen, default

values were used (peak DFR of 25% of the application rate for all crops). For further information

on these default values, refer to the PMRA’s Science Policy Note SPN2014-02, Estimating

Dislodgeable Foliar Residues and Turf Transferable Residues in Occupational and Residential

Postapplication Exposure Assessments.

For workers entering a treated site, restricted-entry intervals (REIs) are calculated to determine

the minimum length of time required before people can safely enter after application. An REI is

the duration of time that must elapse before residues decline to a level where performance of a

specific activity results in exposures above the target MOE.

Postapplication exposure would be primarily via the dermal route. Based on the vapour pressure

of pyriproxyfen, inhalation exposure would be low, provided that the minimum 12-hour REI is

followed.

The postapplication exposure assessment is outlined in Appendix IV, Table 2. At a 12-hour REI,

postapplication risks to workers performing activities such as thinning, pruning, and harvesting,

were shown to be acceptable.

Indoor Structures and Pet Uses

For indoor structural uses and for pet uses, there is potential for short- to intermediate-term

exposure for workers entering treated areas or handling treated pets.

Exposure for postapplication workers in these scenarios was assessed qualitatively. It was

assumed that risks to postapplication workers in these scenarios would be similar to or less than

residential postapplication risks, since time spent in residential areas or time spent handling pets

in the home is assumed to be longer than the respective times in workplaces. Risks were shown

to be acceptable for residential postapplication scenarios for adults after commercial applications

in homes and after handling treated pets (see Section 3.4.2). Based on the exposure

considerations above, risks are expected to be acceptable for workers as well.

3.5 Aggregate Exposure and Risk Assessment

Aggregate exposure is the total exposure to a single pesticide that may occur from food, drinking

water, residential, and other non-occupational sources, and from all known or plausible exposure

routes (oral, dermal and inhalation).

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3.5.1 Toxicology Reference Values for Aggregate Risk Assessment

Short- and Intermediate-term Aggregate

For short- and intermediate-term aggregate assessment for adults, the oral developmental toxicity

study in rabbits was selected. A NOAEL of 100 mg/kg bw/day was established. At 300 mg/kg

bw/day, an increase in abortions/premature deliveries was observed in the presence of maternal

toxicity. This finding was considered relevant for all routes of exposure. Standard uncertainty

factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies variability, along

with a PCPA factor of threefold, as discussed in the Pest Control Products Act Hazard

Characterization Section, resulted in a target MOE of 300.

For short and intermediate-term aggregate assessment for children, the oral developmental

toxicity study in rats that included a postnatal phase was selected. A NOAEL of 100 mg/kg

bw/day was established. At 300 mg/kg bw/day, pup weight was reduced along with an equivocal

reduction in pup viability. This finding was considered relevant for all routes of exposure.

Standard uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies

variability, along with a PCPA factor of onefold, as discussed in the Pest Control Products Act

Hazard Characterization Section, resulted in a target MOE of 100.

3.5.2 Residential and Dietary Aggregate Exposure and Risk Assessment

In an aggregate risk assessment, the combined potential risk associated with food, drinking water

and various residential exposure pathways is assessed. A major consideration is the likelihood of

co-occurrence of exposures and durations of exposures.

Aggregate assessments were conducted for the following short-to-intermediate term scenarios

which are expected to co-occur:

• Following commercial application to control fleas in residential areas:

o Postapplication dermal exposure to adults and children + incidental oral exposure

to children + dietary exposure (food only) for adults and children

• Following application of a domestic-class product indoors to control fleas and ticks:

o For adults, applicator dermal and inhalation exposure + postapplication dermal

exposure + dietary exposure (food only)

o For children, postapplication dermal exposure + incidental oral exposure +

dietary exposure (food only)

• Following application of a domestic-class product to pets:

o For adults, applicator dermal and inhalation exposure + postapplication dermal

exposure + dietary exposure (food only)

o For children, postapplication dermal exposure + incidental oral exposure +

dietary exposure (food only)

Calculated MOEs for aggregate exposure to pyriproxyfen exceeded target MOEs and therefore,

risk is shown to be acceptable. The aggregate risk assessment is outlined in Appendix VI,

Table 1.

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3.6 Cumulative Assessment

The Pest Control Products Act requires that the PMRA considers the cumulative exposure to

pesticides with a common mechanism of toxicity. For the current re-evaluation, the PMRA did

not identify information indicating that pyriproxyfen shares a common mechanism of toxicity

with other pest control products. Therefore there is no requirement for a cumulative risk

assessment at this time.

3.7 Incident Reports

As of 6 December 2018, the PMRA had received 73 human and 6058 domestic animal incidents

involving pyriproxyfen. The pyriproxyfen products reported in incidents are mostly co-

formulated with other active ingredients (for example, synthetic pyrethroids, pyrethrins,

imidacloprid).

Forty-nine human incidents were considered to be possibly related to the reported pyriproxyfen

product. The co-formulated pyriproxyfen products reported in incidents involved companion

animal spot-on products and indoor sprays or foggers. Minor skin and eye irritation were the

most common signs in people and the reported exposure scenarios include treating pets, coming

in contact with treated pets or indoor areas, and during product application. There were six

serious American incidents with co-formulated pyriproxyfen products. Signs reported in these

incidents include effects such as temporary blindness, respiratory distress or muscular weakness.

The described exposure scenarios include ocular exposure when treating a pet, excessive

application of a pesticide, applying a product in non-ventilated areas or living in treated areas. In

one serious American incident involving cardiac arrest and death, the label directions of the

American product were not followed.

The domestic animal incidents mainly involved spot-on pyriproxyfen products registered for use

on cats and dogs (5967 reports). The review of spot-on incidents involving pyriproxyfen and the

proposed mitigation measures for all spot-on products are discussed under Regulatory Proposal

PRO2018-01, Consultation on Proposed Regulatory Changes for Pesticide Products Used on

Companion Animals. Of the remaining 91 incidents, the majority were considered to be possibly

related to the reported pyriproxyfen product. Three minor incidents occurred in the Canada, while

the remainder were serious American incidents mainly involving cats. The reported exposure

scenarios include treatment with an American shampoo containing a pyriproxyfen formulation

not registered for use in Canada or exposure to an indoor spray/powder. The minor signs reported

in animals include symptoms such as drooling, lethargy, anorexia or vomiting. In animals that

died, reported signs include more serious effects like ataxia or convulsion.

Overall, the review of incident reports suggests that the synthetic pyrethroids and/or pyrethrins

present in the co-formulated pyriproxyfen products may have contributed to the adverse effects

reported in people and animals. The labels of Canadian pyriproxfen spot-on products reported in

incidents have protective measures (in other words, use of rubber gloves), as well as

precautionary statements, to minimize the likelihood of exposure in people. Domestic class

Canadian pyriproxyfen products registered for use in indoor areas are co-formulated with the

synthetic pyrethroids, d-phenothrin or tetramethrin. A trend analysis conducted on incidents

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involving synthetic pyrethroid products (2011 Report on Pesticide Incidents), including those

containing d-phenothrin and tetramethrin, identified concerns pertaining to inhalation and dermal

exposure of people and animals following or during the treatment of indoor areas. Label

amendments as outlined in PRO2018-04, Structural Pest Control Products: Label Updates are

therefore proposed to minimize the likelihood of human or animal exposure to pyriproxyfen

products co-formulated with synthetic pyrethroids.

4.0 Environmental Assessment

4.1 Fate and Behaviour in the Environment

Pyriproxyfen is sparingly soluble in water and is hydrolytically stable. Pyriproxyfen is not

expected to volatilize from dry or moist surfaces and, based on an adsorption/desorption study, is

immobile in soil. Pyriproxyfen is non-persistent in aerobic soil under laboratory and field

conditions. Biotransformation is the principal route of dissipation in soil. No major

transformation products are formed. Considering its immobility and non-persistence in soil and

its low water solubility, pyriproxyfen is not expected to leach into groundwater. Pyriproxyfen is

also non-persistent in aerobic water, but was shown to be persistent under anaerobic water

conditions. Pyriproxyfen is not expected to bioaccumulate in organisms.

4.2 Environmental Risk Characterization

The environmental risk assessment integrates the environmental exposure and ecotoxicology

information to estimate the potential for adverse effects on non-target species. This integration is

achieved by comparing exposure concentrations with concentrations at which adverse effects

occur. For greenhouse uses of pyriproxyfen, potential exposure was assessed for beneficial

arthropods and pollinators (typically those used inside greenhouses for production purposes) and

aquatic organisms (potential for exposure of adjacent aquatic habitats to discharge of process

waters from the greenhouse), and a qualitative risk assessment was considered.

4.2.1 Risks to Terrestrial Organisms

Based on the current use pattern (indoor use), minimal exposure to earthworms, birds, wild

mammals, and non-target terrestrial vascular plants is expected. Pyriproxyfen is an insect growth

regulator and effects on beneficial terrestrial invertebrates (bees, predatory and parasitic

arthropods) are expected. For greenhouse uses, a label statement to inform users of potential risks

to beneficial non-target invertebrates is already present on the label. No additional risk reduction

measures are proposed.

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4.2.2 Risks to Aquatic Organisms

Pyriproxyfen is highly toxic to freshwater invertebrates, freshwater fish, estuarine/marine fish,

and is very highly toxic to estuarine/marine invertebrates. Based on the current indoor use

pattern, direct exposure of pyriproxyfen to aquatic organisms is not expected. However, the

potential for indirect exposure to the discharge of greenhouse process water was considered.

Therefore, to minimize the potential exposure of aquatic organisms from the discharge of

greenhouse process water, the current label for the end-use product includes use directions

prohibiting the discharge of greenhouse process water.

In conclusion, the potential risks to non-target terrestrial and aquatic organisms from

pyriproxyfen are considered to be acceptable when the associated end-use products are used

according to the label directions. However, for consistency and to meet current labelling

standards, environmental precaution/disposal statements are proposed to be updated. For

additional details on the environmental assessment of pyriproxyfen, please refer to Proposed

Regulatory Decision Document PRDD2006-04, Pyriproxyfen and Registration Decision

RD2007-03, Pyriproxyfen.

4.2.3 Environmental Incident Reports

As of 19 March 2019, one environment incident involving pyriproxyfen has been submitted to

the PMRA database. A queen bee mortality incident was received by the PMRA in 2018

associated with a pet treatment product which contains three active ingredients (including

pyriproxyfen). A causality assessment concluded that exposure to pyriproxyfen was unlikely to

have contributed to the mortality observed.

The United States EIIS database was also searched for environment incidents in the United States

(data as of October 2015). There were two incidents involving honey bees. One incident was

assigned the certainty index of ‘possible’ while the other was considered as ‘unlikely’. In the

incident considered as possible, the reported product use site was an almond orchard where 2000

bee hives were impacted. No other details were available. These incidents occurred at outdoor

sites, which are not relevant to currently registered uses in Canada.

No additional mitigation measures are recommended based on the review of environmental

incident reports.

5.0 Value Assessment

Pyriproxyfen is a valuable tool for the management of whiteflies, an economically important pest

in greenhouse vegetable and ornamental production. It is mainly used at the end of a production

cycle, to reduce whitefly populations before the next production cycle. For greenhouse

vegetables, it is generally not applied when the fruit are present, but applied when the harvest is

complete, and the vegetative part of the plant is still present. Since whitefly feeding can adversely

affect the appearance and hence marketability of vegetables and ornamentals, maintaining high

quality and visual appeal is critical to these sectors.

Proposed Re-evaluation Decision - PRVD2019-10

Page 25

Pyriproxyfen is a valuable tool for the control of fleas in indoor, non-food areas of structures.

Pyriproxyfen is also co-formulated with other insecticides to broaden the pest spectrum,

including control of ticks in structures, on furniture and carpets.

Pyriproxyfen contributes to the management of companion animal pests (for example, fleas,

ticks, lice and mosquitoes) due to its long residual activity (5 months).

6.0 Pest Control Product Policy Considerations

6.1 Assessment of the Active Ingredient under the Toxic Substances Management Policy

The Toxic Substances Management Policy (TSMP) is a federal government policy developed to

provide direction on the management of substances of concern that are released into the

environment. The TSMP calls for the virtual elimination of Track 1 substances, in other words,

those that meet all four criteria outlined in the policy: persistent (in air, soil, water and/or

sediment), bio-accumulative, primarily a result of human activity and toxic as defined by the

Canadian Environmental Protection Act. The Pest Control Products Act requires that the TSMP

be given effect in evaluating the risks of a product.

During the review process, pyriproxyfen and its transformation products were assessed in

accordance with the PMRA Regulatory Directive DIR99-03,3 and evaluated against the Track 1

criteria. The PMRA has reached the conclusion that pyriproxyfen and its transformation products

do not meet all of the TSMP Track 1 criteria.

6.2 Formulants and Contaminants of Health or Environmental Concern

During the review process, contaminants in the active ingredient as well as formulants and

contaminants in the end-use products are compared against Parts 1 and 3 of the List of Pest

Control Product Formulants and Contaminants of Health or Environmental Concern.4 The list is

used as described in the PMRA Notice of Intent NOI2005-015 and is based on existing policies

and regulations, including the Toxic Substances Management Policy and Formulants Policy,6 and

taking into consideration the Ozone-depleting Substance Regulations, 1998, of the Canadian

Environmental Protection Act (substances designated under the Montreal Protocol).

The PMRA has reached the conclusion that pyriproxyfen and its end-use products do not contain

any formulants or contaminants identified in the List of Pest Control Product Formulants and

Contaminants of Health or Environmental Concern.

3 DIR99-03, The Pest Management Regulatory Agency’s Strategy for Implementing the Toxic Substances

Management Policy

4 SI/2005-114, last amended on 25 June 2008. See Justice Laws website, Consolidated Regulations, List of

Pest Control Product Formulants and Contaminants of Health or Environmental Concern

5 PMRA's Notice of Intent NOI2005-01, List of Pest Control Product Formulants and Contaminants of

Health or Environmental Concern under the New Pest Control Products Act.

6 DIR2006-02, Formulants Policy and Implementation Guidance Document.

Proposed Re-evaluation Decision - PRVD2019-10

Page 26

The use of formulants in registered pest control products is assessed on an ongoing basis through

the PMRA formulant initiatives and Regulatory Directive DIR2006-02.

7.0 Conclusion of Science Evaluation

Pyriproxyfen is an insect growth regulator belonging to juvenile hormone mimics. Pyriproxyfen

is a valuable tool in the management of white flies in greenhouse vegetable and ornamental

production, flea control in indoor, non-food areas of structures and management of fleas on cats

and dogs.

With respect to human health, the health risks associated with the use of pyriproxyfen and

associated end-use products are acceptable when these products are used according to the

proposed revised label directions (Appendix VI).

When used according to the proposed label directions, potential risks to the environment from

the use of pyriproxyfen and associated end-use products have been shown to be acceptable.

List of Abbreviations

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List of Abbreviations

abs absolute

AD administered dose

ADI acceptable daily intake

ALK alkaline phosphatase

ALT alanine aminotransferase

AR androgen receptor

ARfD acute reference dose

AST aspartate aminotransferase

BUN blood urea nitrogen

bw body weight

bwg bodyweight gain

CAF composite assessment factor

CYP cytochrome P450 enzyme(s)

DEHP di-2-ethylhexyl phthalate

DNA deoxyribonucleic acid

EC10 effective concentration to produce a 10% response

ER estrogen receptor

F0 parental generation

F1 first generation

F2 second generation

fc food consumption

Hct hematocrit

Hgb hemoglobin

hr(s) hour(s)

GD gestation day

kg kilogram(s)

L litre(s)

LABC levator ani-bulbocavernosus muscle complex

LC50 lethal concentration to 50%

LD lactation day

LDH lactate dehydrogenase

LD50 lethal dose to 50%

LOAEC lowest observed adverse effect concentration

LOAEL lowest observed adverse effect level

M molar

MAS maximum average score for 24, 48 and 72 hours

MCH mean cell hemoglobin

MCV mean cell volume

mg milligram(s)

MIS maximum irritation score

mL millilitre(s)

MOE margin of exposure

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NOAEC no observed adverse effect concentration

List of Abbreviations

Proposed Re-evaluation Decision - PRVD2019-10

Page 28

NOAEL no observed adverse effect level

NRI50 neutral red incorporation to 50%

PCPA Pest Control Products Act

PMRA Pest Management Regulatory Agency

PND postnatal day

ppm parts per million

RBC red blood cell

rel relative

S9 metabolic activation

sRBC sheep red blood cells

T3 triiodothyronine

T4 thyroxine

TSH thyroid stimulating hormone

UGT uridine 5'-diphospho-glucuronosyltransferase

μM micromolar

wt weight

wc water consumption

wk(s) week(s)

Appendix I

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Appendix I Lists of Pyriproxyfen Products and Uses

Table 1 Registered Pyriproxyfen Products in Canada as of 1 May 2019 excluding discontinued products or products with a

submission for discontinuation

Registration

Number

Marketing Class

Registrant

Product Name

Formulation Type

Active Ingredient

25105

Technical Grade Active

Ingredient

Sumitomo Chemical

Company Ltd.

SUMILARV TECHNICAL

GRADE

Solid

Pyriproxyfen 98.7%

25489

Manufacturing

Concentrate

McLaughlin Gormley King

Company

NYLAR 50%

CONCENTRATE

Solution

Pyriproxyfen 50%

27545

Rolf C. HAGEN Inc.

PERMETHRIN NYLAR

SQUEEZE ON

MANUFACTURING

BLEND

Solution

Pyriproxyfen 1.9%

Permethrin 45%

27705

ETOFENPROX NYLAR

SQUEEZE ON

MANUFACTURING

BLEND

Pyriproxyfen 2.2%

Etofenprox 55%

25490

Commercial

McLaughlin Gormley King

Company

NYGUARD IGR

CONCENTRATE

Emulsifiable

Concentrate

Pyriproxyfen 10%

28414

VALENT Canada Inc.

DISTANCE

Emulsifiable

Concentrate

Pyriproxyfen 103 g/L

27581

Domestic

BAYER Inc.

ADVANTAGE II SMALL

DOG

Solution

Pyriproxyfen 0.46%

Imidacloprid 9.1%

27582

ADVANTAGE II LARGE

DOG

27583

ADVANTAGE II MEDIUM

DOG

27584

ADVANTAGE II EXTRA

LARGE DOG

27585

ADVANTAGE II SMALL

CAT

27586

ADVANTAGE II LARGE

CAT

29777

K9 ADVANTIX II SMALL

DOG

Pyriproxyfen 0.44%

Permethrin 44%

Imidacloprid 8.8%

29778

K9 ADVANTIX II

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

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Registration

Number

Marketing Class

Registrant

Product Name

Formulation Type

Active Ingredient

MEDIUM DOG

29779

K9 ADVANTIX II EXTRA

LARGE DOG

29780

K9 ADVANTIX II LARGE

DOG

31517

ADVANTAGE II KITTENS

Pyriproxyfen 0.46%

Imidacloprid 9.1%

31119

Domestic

HARTZ Canada Inc.

HARTZ ULTRAGUARD

PLUS FLEA & TICK

HOME SPRAY

Solution

Pyriproxyfen 0.015%

D-phenothrin 0.40%

Piperonyl butoxide

31749

HARTZ ULTRAGUARD

PRO FLEA & TICK

SHAMPOO FOR DOGS

Emulsifiable

Concentrate

Pyriproxyfen 0.075%

D-phenothrin 0.270%

S-methoprene 0.04%

25491

Domestic

McLaughlin Gormley King

Company

NYLAR PRESSURIZED

SPRAY 2618

Pressurized product

Pyriproxyfen 0.015%

D-phenothrin 0.30%

Tetramethrin 0.40%

31941

Domestic

Neogen Corporation

PROZAP PET GUARD IGR

FLEA SPRAY

Pressurized product

Pyriproxyfen 0.015%

D-phenothrin 0.30%

Tetramethrin 0.40%

26179

Domestic

Premier Tech Ltd.

C-I-L FLEA KILLER

SURFACE SPRAY

Pressurized product

Pyriproxyfen 0.015%

D-phenothrin 0.300%

Tetramethrin 0.400%

26502

Domestic

Rolf C. HAGEN Inc.

SERGEANT'S PRETECT

HOUSEHOLD FLEA

SPRAY

Pressurized product

Pyriproxyfen 0.015%

D-phenothrin 0.3%

Tetramethrin 0.4%

28113

SERGEANT'S PRETECT

SQUEEZE-ON FLEA, TICK

& MOSQUITO CONTROL

FOR DOGS (UP TO 15 KG)

Liquid

Pyriproxyfen 1.9%

Permethrin 45%

28280

SEARGEANT'S PRETECT

SQUEEZE-ON FLEA, TICK

& MOSQUITO CONTROL

FOR DOGS (OVER 30 KG)

Solution

28281

SERGEANTS PRETECT

SQUEEZE-ON FLEA, TICK

&MOSQUITO CONTROL

FOR DOGS (15-30 KG)

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

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Registration

Number

Marketing Class

Registrant

Product Name

Formulation Type

Active Ingredient

28610

SERGEANT'S PRE TECT

SQUEEZE-ON FLEA

CONTROL FOR CATS

AND KITTENS

Pyriproxyfen 2.2%

31608

SENTRY FLEA SQUEEZE-

ON FOR CATS AND

KITTENS

31609

SENTRY FLEA, TICK &

MOSQUITO SQUEEZE-ON

FOR DOGS (15 TO 30 KG)

Pyriproxyfen 1.9%

Permethrin 45%

31610

SENTRY FLEA, TICK &

MOSQUITO SQUEEZE-ON

FOR DOGS (OVER 30 KG)

31611

SENTRY FLEA, TICK &

MOSQUITO SQUEEZE-ON

FOR DOGS (UP TO 15 KG)

31647

SENTRY HOUSEHOLD

FLEA SPRAY

Pressurized product

Pyriproxyfen 0.015%

D-phenothrin 0.30%

Tetramethrin 0.40%

32546

SERGEANT'S GUARDIAN

FLEA, TICK & MOSQUITO

CONTROL FOR DOGS (15

TO 30 KG)

Solution

Pyriproxyfen 1.9%

Permethrin 45.0%

32547

SERGEANT'S GUARDIAN

FLEA CONTROL FOR

CATS & KITTENS

Pyriproxyfen 2.2%

32548

SERGEANT'S GUARDIAN

FLEA, TICK & MOSQUITO

CONTROL FOR DOGS

(OVER 30 KG)

Pyriproxyfen 1.9%

Permethrin 45.0%

32549

SERGEANT'S GUARDIAN

FLEA, TICK & MOSQUITO

CONTROL FOR DOGS (UP

TO 15 KG)

Liquid

Pyriproxyfen 1.9%

Permethrin 45.0%

Appendix I

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Table 2 Registered Commercial and Restricted Class Uses of Pyriproxyfen as of 1 May 2019 excluding discontinued products

or products with a submission for discontinuation

Site

Pest(s)

Formulation

type

Application Method

and Equipment

Maximum

Single

Application

Rate

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year

Minimum

Interval

Between

Applications

(Days)

USC 5 – Greenhouse Food Crops

Greenhouse

cucumbers

Greenhouse eggplant

Greenhouse peppers

Greenhouse tomatoes

Silverleaf whitefly,

sweet potato

whitefly,

greenhouse whitefly

Emulsifiable

Concentrate

Ground application –

foliar spray

4.64 g a.i./100L

18.56 g a.i ./100L

2 per crop

Maximum 2

applications

per six months

(4/year)

USC 6 – Greenhouse Non-food Crops

Greenhouse

ornamentals

Silverleaf whitefly,

sweet potato

whitefly,

greenhouse whitefly

Emulsifiable

Concentrate

Ground application –

foliar spray

4.64 g a.i./100L

18.56 g a.i ./100L

2 per crop

Maximum 2

applications

per six months

(4/year)

USC 20 - Structural

Indoor

(Homes, apartment

buildings, Office

Buildings,

Automobiles, Buses,

Boats,

Ship Cabins and

Holds, Trucks,

Boxcars and Non-

Food Areas of Hotels

and Motels)

Fleas

(inhibits growth of

larvae)

Emulsifiable

Concentrate

Broadcast

application, spot and

crack and crevice

application.

Any low pressure

sprayer typically used

for indoor

applications

0.48 g

a.i./100m2

0.96 g a.i./100m2

150

Appendix I

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Table 3 Registered Domestic Class Uses of Pyriproxyfen as of 1 May 2019, excluding discontinued products or products with

a submission for discontinuation1

Site

Pest(s)

Formulations

Application Method and

Equipment

Maximum

Single

Application

Rate

(g a.i./ha)

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year1

Minimum

Interval

Between

Applications1

(Days)

USC 20 – Structural

Indoors

(Homes,

garages, attics

and

apartments.)

Fleas

(larvae) and

ticks

Solution

Fine spray applied

uniformly to carpets, rugs,

pet bedding and all

surfaces of upholstered

furniture where pests are

found.

6.2 mg a.i./m2

12.4 mg a.i./m2

[2]

[182]

Indoors

(Residential and

Commercial

uses)

Fleas

(Adults and

Pre-adult)

Pressurized

Product

Spot and crack-and-

crevice application only

Apply only to localized

areas of flea infestation,

such as pet bedding

6.56 mg

a.i./m2

13.12 mg a.i./m2

[2]

[180]

USC 24 – Companion Animals

Cats

(2.3 kg or less)

(Do not use on

kittens under 8

weeks of age)

Fleas

(larvae,

adult, egg)

Solution

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

1.16 mg

a.i./application

13.9 mg a.i.

Cats

(2.3–4 kg)

(Do not use on

kittens under 8

weeks of age)

2.01 mg

a.i./application

24.12 mg a.i.

Cats

(over 4 kg)

(Do not use on

4.03 mg

a.i./application

48.4 mg a.i.

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

Page 34

Site

Pest(s)

Formulations

Application Method and

Equipment

Maximum

Single

Application

Rate

(g a.i./ha)

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year1

Minimum

Interval

Between

Applications1

(Days)

kittens under 8

weeks of age)

Cats

(4 kg or less)

(Do not use on

kitten under 12

weeks of age)

Fleas (eggs)

Solution

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

34.3 mg

a.i./application

137.2 mg a.i.

Cats

(over 4 kg)

(Do not use on

kitten under 12

weeks of age)

164.6 mg a.i.

4.8

Dogs

(up to 4.5 kg)

(Do not use on

puppies under 7

weeks of age)

Fleas

(larvae,

adult, egg)

and

lice

Solution

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

1.84 mg

a.i./application

22.08 mg a.i.

Dogs

(4.6 –11 kg)

(Do not use on

puppies under 7

weeks of age)

5 mg

a.i./application

60 mg a.i.

Dogs

(11–25 kg)

(Do not use on

puppies under 7

weeks of age)

12.6 mg

a.i./application

151 mg a.i.

Dogs

(over 25 kg)

20.1 mg

a.i./application

241.2 mg a.i.

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

Page 35

Site

Pest(s)

Formulations

Application Method and

Equipment

Maximum

Single

Application

Rate

(g a.i./ha)

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year1

Minimum

Interval

Between

Applications1

(Days)

(Do not use on

puppies under 7

weeks of age)

Dogs

(4.5 kg or less)

(Do not use on

puppies under 8

weeks of age)

Fleas

(larvae,

adult, egg),

ticks

(adults),

mosquitos

(adults) and

lice (adults)

Solution

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

2 mg

a.i./application

24 mg a.i.

Dogs

(4.6 –11 kg)

(Do not use on

puppies under 8

weeks of age)

5 mg

a.i./application

60 mg a.i.

Dogs

(11–25 kg)

(Do not use on

puppies under 8

weeks of age)

12.5 mg

a.i./application

150 mg a.i.

Dogs

(over 25 kg)

(Do not use on

puppies under 8

weeks of age)

20.1 mg

a.i./application

241.2 mg a.i.

Dogs

(Do not use on

puppies under 6

months of age

and nursing

animals)

Fleas

(larvae, egg),

ticks (adults)

Emulsifiable

Concentrate

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

1.7 mg a.i./kg

body

weight./applic

ation

88.4 mg a.i./kg

body weight

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

Page 36

Site

Pest(s)

Formulations

Application Method and

Equipment

Maximum

Single

Application

Rate

(g a.i./ha)

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year1

Minimum

Interval

Between

Applications1

(Days)

Dogs

(up to 15 kg)

(Do not use on

puppies under 3

months)

Fleas,

mosquitoes,

brown dog

ticks,

blacklegged

(deer) ticks

and

American

dog ticks.

Inhibits flea

egg

development

Solution

Place the tip of the

applicator tube on the skin

and squeeze the tube to

completely empty the

contents directly on the

skin as a single spot.

28.5 mg

a.i./application

342 mg a.i.

Dogs

(15–30 kg)

(Do not use on

puppies under 3

months)

57 mg

a.i./application

684 mg a.i.

Dogs

(over 30 kg)

(Do not use on

puppies under 3

months)

85.5 mg

a.i./application

1026 mg a.i.

Dogs

(up to 15 kg)

(Do not use on

puppies under 3

months of age

and nursing

animals)

32.5 mg

a.i./application

390 mg a.i.

Dogs

(15–30 kg)

(Do not use on

puppies under 3

months of age

and nursing

animals)

65 mg

a.i./application

780 mg a.i.

Appendix I

Proposed Re-evaluation Decision - PRVD2019-10

Page 37

Site

Pest(s)

Formulations

Application Method and

Equipment

Maximum

Single

Application

Rate

(g a.i./ha)

Maximum

Cumulative

Application Rate

per Year

Maximum

Number of

Applications

per year1

Minimum

Interval

Between

Applications1

(Days)

Dogs

(over 30 kg)

(Do not use on

puppies under 3

months of age

and nursing

animals)

97.6 mg

a.i./application

1171.2 mg a.i.

1 Information in Square [ ] brackets is based upon consultation with the registrant

Appendix II

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Page 38

Appendix II Toxicological Information for Health Risk Assessment

Table 1 Chemical Names of Pyriproxyfen and Select Metabolites

Compound

Identifier

Chemical Name

pyriproxyfen

4-phenoxyphenyl (RS)-2-(2-pyridyloxy) propyl ether

4'-OH -pyr

4-(4-hydroxyphenoxy)phenyl (RS)-2-(2-pyridyloxy)propyl ether

2'-OH-pyr

4-(2-hydroxyphenoxy)phenyl (RS)-2-(2-pyridyloxy)propyl ether

5",4'-OH-pyr

4-(4'-hydroxyphenoxy)phenyl (RS)-2-(5-hydroxypyridyl-2-oxy)propyl

ether

5"-OH-pyr

(RS)-5-hydroxy-2-{1-methyl-2-(4-phenoxyphenoxy)}ethoxy pyridine

DPH-pyr

4-hydroxyphenyl (RS)-2-(2-pyridyloxy)propyl ether

PYPA

(RS)-2-(2-pyridyloxy)propanol

PYPAC

(RS)-2-(2-pyridyloxy)propionic acid

2-OH-py

2-hydroxypyridine

POPA

4-phenoxyphenyl (RS)-2-hydroxypropyl ether

4'-OH-POPA

4-(4-hydroxyphenoxy)phenyl (RS)-2-hydroxypropyl ether

4'-OH-POP

4,4'-oxydiphenol

2,5-OH-py

2,5-hydroxypyridine

Table 2 Summary of Toxicology Studies for Pyriproxyfen

NOTE: Effects noted below are known or assumed to occur in both sexes unless otherwise noted;

in such cases, sex-specific effects are separated by semi-colons. Effects on organ weights are

known or assumed to reflect changes in absolute weight and relative (to bodyweight) weight

unless otherwise noted.

Study Type/

Animal/PMRA #

Study Results

Toxicokinetic Studies

Sprague Dawley Rat

PMRA# 1143941, 1143949,

1159016

Sprague Dawley rats were given a single oral dose of 2 mg/kg bw or 1000

mg/kg bw [phenyl-14C] pyriproxyfen, or a single oral dose of 2 mg/kg bw

[phenyl-14C] pyriproxyfen following oral administration of 2 mg/kg bw/day

unlabelled pyriproxyfen over two weeks; excreta were collected over 7 days.

Additionally, Sprague Dawley rats were given a single oral dose of 2 mg/kg

bw [phenyl-14C] pyriproxyfen and tissues were sampled at 2, 4, 8, 12, 24, 48

and 72 hrs.

Absorption: Based on urine concentration data, pyriproxyfen was not well-

absorbed. Peak blood levels following a single low dose were noted at 2 hrs

(♂) or 2–24 hrs (♀); ♂ showed 4-fold higher 14C concentrations in blood

than ♀ until 24 hrs after administration.

Distribution: In ♂ and ♀ rats, the maximum total tissue 14C residue

concentrations were 7.3% and 5.2% of the AD respectively, 8 hrs following

a single oral low dose. Maximum tissue concentrations were highest in liver,

blood (♂ only), kidneys and adipose tissues. The

C levels in adipose tissue

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 39

Study Type/

Animal/PMRA #

Study Results

were the highest tissue levels after 7 days. All other non-adipose tissues

contained 14C residue concentrations of ≤0.001, ≤0.6, and ≤0.003 ppm for

the low, high, and repeated-dose groups, respectively. There were no

significant sex or dose-related differences in tissue distribution.

Sprague Dawley Rat

PMRA# 2704562

PMRA #2704562 – Sprague Dawley rats were administered [pyridyl-2,6-

14C] pyriproxyfen as single oral doses of 2.0 mg/kg bw or 1000 mg/kg bw;

urine and feces were collected for 7 days. Additional ♂ rats were orally

dosed with [phenyl-14C] pyriproxyfen, from which urine and feces were

collected for 2 days.

Absorption: Based on urine concentration data, pyriproxyfen was not well-

absorbed.

Distribution: Tissues accumulated very little radioactivity; fat contained the

greatest amount at 0.024 - 0.042% of the AD 7 days after dosing; no dose or

sex difference was noted.

Excretion: Pyriproxyfen was rapidly eliminated with >85% of the AD

eliminated in the first 48 hrs, primarily in the feces. After 7 days, >84% of

the AD was in the feces and up to 12% was in the urine. Small amounts of

radioactivity were detected in expired air (≤0.5% of the AD). There were no

effects of sex, dose or label position on elimination.

Metabolism: Metabolite analyses were conducted using urine and feces

collected during the first 48 hrs after dosing; The major fecal metabolite was

4'-OH-pyr, comprising 23–47% of the AD. Unchanged pyriproxyfen in feces

accounted for 21–35% of the AD. Minor fecal metabolites included 2'-OH-,

5''-OH-, and 5'', 4'-OH-pyr. Sulfate conjugates of 4'-OH and 5'', 4'-OH-pyr

and a glucuronide conjugate of the 4'-OH-pyr were detected. 5'', 4'-OH-pyr

was detected in low-dose ♂ at 7.2% of the AD; all other minor fecal

metabolites and conjugates were detected at ≤4% in both sexes at each dose.

DPH-pyr, a product of cleavage of the terminal phenyl ring was present in

feces at <2% of the AD. Unchanged pyriproxyfen and 4'-OH-pyr were

detected in minor amounts in the urine of high-dose rats (1–3% and 1–6%

respectively), but were absent in urine of the low-dose rats. PYPAC, a

pyridyl metabolite from cleavage of both phenyl rings was present in urine at

1–5%, but was not detected in feces. Minor amounts of the sulfate

conjugates were detected in urine.

The major pathway of pyriproxyfen metabolism in rats involves

hydroxylation at the 4'-position of the terminal phenyl ring. Minor pathways

include hydroxylation at the 2'-position of the terminal phenyl ring and at the

5''-pyridyl position, dephenylation, cleavage of ether linkages, and formation

of glucuronide and sulfate conjugates. There were no significant effects of

sex or dose on the metabolic pattern of pyriproxyfen.

Acute Toxicity Studies

Acute Oral

Sprague Dawley Rat

PMRA #1143889, 1159046

Low toxicity

LD50 > 5000 mg/kg bw (corn oil)

No deaths. Clinical signs (↓ spontaneous activity, soft faeces, diarrhea, ↓

bwg at ≥ 2500 mg/kg bw) resolved within 2 days.

Acute Dermal

Sprague Dawley Rat

Low toxicity

LD50 > 2000 mg/kg bw (corn oil)

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 40

Study Type/

Animal/PMRA #

Study Results

PMRA #1143893, 1159057

No deaths or clinical signs of toxicity.

Acute Inhalation (4 hr,

whole body)

Sprague Dawley Rat

PMRA #1143894, 1159068,

2704564

Slight toxicity

LC50 >1.3 mg/L (corn oil)

1.3 mg/L: Transient clinical signs of toxicity, salivation (2/5 ♂ and 1/5 ♀);

urinary incontinence (♀).

Primary Skin Irritation

NZW Rabbit

PMRA #1143896

Non-irritating.

MAS = 4.5 (24, 48 and 72 hrs)

Primary Eye Irritation

NZW Rabbit

PMRA #1143896

Minimally irritating.

MIS = 4.7 (at 1 hr)

Skin Sensitization

(Maximization method)

Hartley Guinea Pig

PMRA #1143897

Not a dermal sensitizer.

Short-Term Toxicity Studies

21-Day Dermal

Sprague Dawley Rat

PMRA #1164979

NOAEL = 1000 mg/kg bw/day (corn oil)

No compound-related changes were noted.

28-Day Inhalation

(whole-body)

Sprague Dawley Rat

PMRA #1143883

NOAEC = 0.482 mg/L (84 mg/kg bw/day)(♂); 1 mg/L (174 mg/kg

bw/day)(♀)

1.00 mg/L (174 mg/kg bw/day): salivation during initial exposures; ↓ bw, ↑

LDH, ↓ abs lung wt (♂); ↑ wc (♀).

90-Day Oral

(dietary)

CDBR Rat

PMRA #1143899, 1159075

NOAEL = 400 ppm (24/28 mg/kg bw/day in ♂/♀)

≥2000 ppm (118/141 mg/kg bw/day): cytoplasmic change consisting of ↑ in

cytoplasmic content, ↓nucleus/cytoplasm ratio and ↓ sinusoidal space; ↓

RBC, ↓ Hgb, ↓Hct, ↑ cholesterol, ↑ phospholipid, ↑ rel liver wt (♂); ↓MCV

(♀).

≥5000 ppm (309/356 mg/kg bw/day): ↓ bw, ↑ liver wt; ↑ rel kidney wt (♂);

↓ RBC, ↓ Hgb, ↓Hct, ↑ cholesterol (♀).

10 000 ppm (642/784 mg/kg bw/day): ↑ total protein, ↑ albumin; ↑

phospholipid, ↑ rel kidney wt (♀).

90-Day Oral

(dietary)

NOAEL = 1000 ppm (149/197 mg/kg bw/day in ♂/♀)

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 41

Study Type/

Animal/PMRA #

Study Results

CD-1 Mouse

PMRA #1164978

≥5000 ppm (838/964 mg/kg bw/day): hunched posture, few or no feces,

↓Hgb, ↓ Hct, ↑ platelets, ↑ wc, ↑ BUN, ↑ rel liver wt, renal effects (tubular

nephrosis, dilation of renal tubules and pelvis, focal mineralization); ↑

mortality, ↓ bw, ↓ bwg, ↑ rel adrenal gland wt, ↓ MCV, ↓ MCH, ↑ AST, ↑

ALT, thymic lymphoid depletion, bone marrow myeloid hyperplasia, ↑

spleen pigmentation (♂); thin appearance, ↓ RBC, ↑ cholesterol, ↑

phospholipids, ↑ abs liver wt (♀).

10,000 ppm (2035/2345 mg/kg bw/day): myeloid hyperplasia of bone

marrow, cardiomyopathy, thymic atrophy; ↓ RBC, mortality, ↓ bw, thymic

lymphoid depletion, ↑ spleen pigmentation, extra medullary hematopoiesis

(♀).

90-Day Oral

(capsule)

Beagle Dog

PMRA #1143898

NOAEL = 100 mg/kg bw/day (♀); 300 mg/kg bw/day (♂)

≥300 mg/kg bw/day: ↑ liver wt; hepatocellular enlargement, ↑ cholesterol, ↑

phospholipid (♀).

1000 mg/kg bw/day: hepatic cytoplasmic changes (eosinophilic bodies, ↑ in

smooth endoplasmic reticulum proliferation, dilation of endoplasmic

reticulum); hepatocellular enlargement (♂).

52-Week Oral

(capsule)

Beagle Dog

PMRA #1143882, 2704560,

1159076

NOAEL = 30 mg/kg bw/day (♂); 100 mg/kg bw/day (♀)

≥30 mg/kg bw/day: ↑ rel liver wt (♂).

≥100 mg/kg bw/day: ↓ bwg, ↑ cholesterol, ↑ liver wt; ↓bw, ↑ triglycerides, ↑

ALK in one animal (♂)

≥300 mg/kg bw/day: ↑ ALK; thin appearance, ↑ platelets, submucosal

fibrosis of the gall bladder (♂); ↓ bw, ↑ triglycerides, ↑ rel kidney wt, ↑

thyroid wt (♀).

1000 mg/kg bw/day: salivation, diarrhea, emesis, ↑ ALT, centriacinar

fibrosis, bile duct hyperplasia, active chronic inflammatory infiltrate,

submucosal edema of the gall bladder; 2 mortalities (sacrificed due to

toxicity), bw loss, ↑ prothrombin time, ↑ AST, ↑ bilirubin, ↑ urinary volume,

↓ pH, nodular hyperplasia, (♂); ↑ platelets, submucosal fibrosis of the gall

bladder (♀).

52-Week Oral

(capsule)

Beagle Dog

PMRA #2704560

NOAEL = 10 mg/kg bw/day

≥3 mg/kg bw/day: slight ↑ platelets (♂).

10 mg/kg bw/day: slight ↑ platelets (♀).

Chronic Toxicity/Oncogenicity Studies

78-Week Oncogenicity

(dietary)

CD-1 Mouse

PMRA #1143912, 1143930,

1159013, 1169747, 2704561

NOAEL = 120 ppm (16 mg/kg bw/day) (♂); 600 ppm (107 mg/kg

bw/day)(♀)

≥120 ppm (16/21 mg/kg bw/day: hunched posture.

≥600 ppm (79/107 mg/kg bw/day): ↓ survival after week 64, ↑ severity of

amyloidosis in kidneys, thyroid, parathyroid and stomach of decedents (♂).

3000 ppm (413/530 mg/kg bw/day): ↓ bw, granular/pitted/rough kidneys,

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 42

Study Type/

Animal/PMRA #

Study Results

accelerated development and severity of amyloidosis (multi-tissue), ↑

incidence of chronic progressive nephropathy, ↑ incidence of mineralized

renal tubules; ↓ survival after week 60, ↓ motor activity, ↓ bwg up to wk 24,

↓ abs kidney wt at termination (♂); ↓ survival after wk 64, ↓ bwg,

erythrocyte changes at wk 52 (↓ Hgb, slight ↓ RBC, slight ↓ Hct, ↑

polychromatic RBC), ↑ liver wt at wk 52, ↑ abs spleen wt at wk 52 (♀).

No evidence of carcinogenicity.

2-Year Chronic

Toxicity/Oncogenicity

(dietary)

Sprague Dawley Rat

PMRA #1143884, 1143902,

1143903, 2704559,

2704558, 1159077, 1164935

NOAEL = 600 ppm (27/35 mg/kg bw/day)

≥600 ppm (27/35 mg/kg bw/day: ↓ urinary pH at wk 26 (♀)(non-adverse).

3000 ppm (138/183 mg/kg bw/day): ↓ bw, ↓bwg, ↑ phospholipid and

cholesterol at wk 26; ↑ cholesterol wks 52, 78 (♂); ↑ urinary protein at wk

26, ↑ rel liver wt at interim and terminal sacrifice (♀).

No evidence of carcinogenicity.

Developmental/Reproductive Toxicity Studies

Two-generation

Reproductive Toxicity

(dietary)

Sprague Dawley Rat

PMRA #1143904, 1143905

Parental

NOAEL = 1000 ppm (64/103 mg/kg bw/day)

≥1000 ppm (80 mg/kg bw/day): ↑ rel liver wt, ↑ rel kidney wt (F1♂).

5000 ppm (328/531 mg/kg bw/day): ↓ bw (pre-mating, F0, F1), ↓ bwg (pre-

mating, F0, F1), sporadic ↓ fc, ↑ liver wt (F1); chronic interstitial nephritis,

focal clear cells in liver (F1 ♂).

Offspring

NOAEL = 1000 ppm (103 mg/kg bw/day)

5000 ppm (531 mg/kg bw/day): ↓ pup bw PND 14 and 21 (F1 and F2).

No evidence of increased sensitivity of the young.

Reproductive

NOAEL = 5000 ppm (328/531 mg/kg bw/day)

No effect on reproductive parameters.

Reproductive/Developmental

Toxicity – non-guideline

(gavage)

Sprague Dawley Rat

PMRA #2704582

Exposure from 9-weeks pre-

mating to GD 7 and

examination of fetuses at GD

Parental

NOAEL = 100 mg/kg bw/day

≥100 mg/kg bw/day: transient salivation immediately following dosing; ↑

wc, ↑ rel liver wt, ↑ rel kidney wt, ↑ adrenal wt (♂).

≥300 mg/kg bw/day: erythema, ↓ bwg; ↓ bw, ↑ fc, ↓ thymus wt, ↑ abs liver

wt, ↑ abs kidney wt, enlargement of the liver, dark-red colour of the liver,

pitted surface of the kidney, enlargement of the adrenals (♂); diarrhea,

swelling of the periproctal region, ↑ wc during gestation (♀).

≥500 mg/kg bw/day: diarrhea, swelling of the periproctal region,

enlargement of the kidney (♂); ↑wc during pre-mating (♀).

1000 mg/kg bw/day: lacrimation, atrophy of the thymus (♂); mortality in 2

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 43

Study Type/

Animal/PMRA #

Study Results

animals, ↓ bw, ↑fc during gestation, hypoactivity, wasting (♀).

Developmental

NOAEL = 1000 mg/kg bw/day

No effects on fetal weight, sex or development.

Reproductive

NOAEL = 500 mg/kg bw/day

1000 mg/kg bw/day: ↓ number of corpora lutea per dam.

No evidence of sensitivity of the young.

Developmental Toxicity

(gavage)

Sprague Dawley Rat

PMRA #1143907, 1159015

Exposure from GD 7-17,

examination of fetuses at GD

21 and pups at 3 weeks

(general toxicity), 8 weeks

(open field test, motor co-

ordination test and learning

ability) and 11 weeks

(reproductive performance)

Maternal

NOAEL = 100 mg/kg bw/day

100 mg/kg bw/day: transient ↓ bwg.

≥300 mg/kg bw/day: ↓ bw, ↓ bwg, ↓ fc, ↑ wc, ↑ rel liver wt, ↑ rel kidney wt.

1000 mg/kg bw/day: ↑ mortality (all deaths occurring after 4-9 doses), soft

stool, erythema, swelling of the periproctal region, bw loss in first few days

of dosing, ↑ adrenal wt, ↓ thymus wt, ↓ abs spleen wt, ↓ abs heart wt, ↑ abs

kidney wt, adrenal enlargement (GD 21), thymic involution (GD 21), ↑ early

resorptions (attributable to 100% resorptions in 2 dams).

Dams that died showed hypoactivity, wasting, bloody dirtiness around the

nose, blanching of the auricle and extremities, hypothermia, kidney and liver

congestion, splenic atrophy, adrenal enlargement, thymic involution,

stomach haemorrhage or ulceration.

Developmental/Offspring

NOAEL = 100 mg/kg bw/day

≥300 mg/kg bw/day: ↑ incidence of opening of the 7th cervical vertebra

foramen transversium, ↑ total incidence of skeletal variations in 3-wk-old

pups.

1000 mg/kg bw/day: ↑ total fetal incidence of skeletal variations, ↑

incidence of renal pelvis dilatation in 3- and 8-wk-old pups, ↑ rel kidney wt

in 8-wk-old ♀ pups.

No effects on sensory function, behaviour, motor coordination or learning

ability in pups.

Reproductive

NOAEL = 1000 mg/kg bw/day

No effects on reproductive performance in pups.

No evidence of sensitivity of the young. Not teratogenic.

Reproductive/Developmental

Toxicity

(gavage)

Maternal

NOAEL = 100 mg/kg bw/day

≥300 mg/kg bw/day: diarrhea, salivation, ↓bw (GD 20-22), ↓fc (GD 19-22,

Appendix II

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Page 44

Study Type/

Animal/PMRA #

Study Results

Sprague Dawley Rat

PMRA #2704580

Exposure from GD 17-

LD20, examination of pups

at PND 4 (skeletal

anomalies), 3 weeks (general

toxicity), 8 weeks (open field

test, motor co-ordination test

and learning ability) and 11

weeks (reproductive

performance)

LD21), ↑liver wt.

500 mg/kg bw/day: mortality (2 dams after 5 doses), erythema and swelling

of the periproctal region, hypoactivity, lacrimation, rough hair, hypothermia,

atrophy of the thymus, congestion of liver, atrophy of spleen and adrenals,

ulcers of the stomach.

Offspring

NOAEL = 100 mg/kg bw/day

≥300 mg/kg bw/day: ↓pup weight (PND 0-56), ↑incidence of dilatation of

the renal pelvis, equivocal ↓viability index at PND 21.

500 mg/kg bw/day: ↓viability index at PND 4 and 21 (F1), slight delay in

vaginal opening (F1).

No effects on sensory function, behaviour, motor coordination or learning

ability in pups.

Reproductive

NOAEL = 100 mg/kg bw/day

300 mg/kg bw/day: ↓pup birth wt (F1)

500 mg/kg bw/day: ↓ mean implantations (F1), ↑pre-implantation loss (F1),

↓livebirth index (F1), ↓litter size (F1).

No evidence of sensitivity of the young.

14-Day Toxicity

(gavage)

JW NIBS Rabbit (non-

pregnant)

PMRA #2704576

Range-finding study - supplemental

1000 mg/kg bw/day: ↓ bw, ↓ bwg, ↓ fc.

Developmental Toxicity

(gavage)

JW-NIBS Rabbit

PMRA #1143906, 1159014,

1164980

Maternal

NOAEL = 100 mg/kg bw/day

≥300 mg/kg bw/day: ↓ bwg, ↓ fc, late abortions/ premature deliveries, in

dams that aborted, delivered prematurely or died: soft stool, emaciation,

lustreless fur, ↓ activity, bradypnea, abnormally coloured intestinal contents,

gall bladder distention, watery/abnormally coloured bile, trace gastro-

intestinal haemorrhage and gas retention, and kidney discolouration were

observed.

1000 mg/kg bw/day: ↓ bw, bw loss (GD 6-18), mortality, splenic

congestion.

Developmental

NOAEL = 300 mg/kg bw/day

1000 mg/kg bw/day: ↑ incidence of abnormal location of posterior vena

cava.

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 45

Study Type/

Animal/PMRA #

Study Results

No evidence of increased sensitivity of the young. Not teratogenic.

Note: litters available for examination were 13, 12, 11 and 4 at 0, 100, 300,

1000 mg/kg bw/day respectively.

Genotoxicity Studies

In vitro Bacterial Reverse

Mutation Assay

Salmonella typhimurium

strains TA 98, TA 100, TA

1535, TA 1537 and TA

1538;

E. Coli WP2uvrA

PMRA #1143910

Negative with and without activation.

In vitro Mammalian Gene

Mutation Assay

Chinese hamster V79 lung

cells

PMRA #1143911

Negative with and without activation.

In vitro Unscheduled DNA

Synthesis Assay

HeLa S3 cells

PMRA #1143909

Negative with and without activation.

In vitro Chromosome

Aberration Assay

Chinese hamster ovary cells

(CHO-K1)

PMRA #1143908

Negative with and without activation.

In vivo Micronucleus Assay

CD-1 Mouse

PMRA #621875

Negative at 5000 mg/kg bw (corn oil).

Neurotoxicity Studies

Acute Neurotoxicity

(gavage)

Sprague Dawley Rat

PMRA #2704596

Range-finding study - supplemental

No treatment-related findings were noted up to and including 2000 mg/kg

bw.

Acute Neurotoxicity

(gavage)

Sprague Dawley Rat

PMRA #2704607

NOAEL = 300 mg/kg bw (♂), 1000 mg/kg bw (♀)

≥1000 mg/kg bw: ↓ motor activity at 8 hrs post-dosing (♂).

2000 mg/kg bw: unkempt appearance on day 1 post-dosing (♀).

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 46

Study Type/

Animal/PMRA #

Study Results

90-Day Neurotoxicity

(dietary)

Sprague Dawley Rat

PMRA #2704606

Range-finding study - supplemental

≥7500 ppm (691/762 mg/kg bw/day): ↓ bw, ↓ bwg, ↓ fc (♂).

15000 ppm (1359/1468 mg/kg bw/day): ↓ bw, ↓ bwg (♀).

90-Day Neurotoxicity

(dietary)

Sprague Dawley Rat

PMRA #2704608

NOAEL = 5000 ppm (359/407 mg/kg bw/day)

15000 ppm (1111/1212 mg/kg bw/day): ↓ bw, ↓ bwg, ↓ fc.

No evidence of neurotoxicity.

Special Studies (non-guideline)

28-Day Immunotoxicity

(dietary)

CD-1 Mouse

PMRA #2704592

Range-finding study

≥4000 ppm (with and without sRBC): slight bw loss or ↓ bw gain in first

four days of dosing, ↓ fc in first wk of dosing, ↑ liver wt.

7000 ppm (with and without sRBC): hunched posture, dull eyes,

piloerection, bw loss, ↓fc, ↑ phospholipid, ↑ cholesterol, ↑ plasma creatinine,

↑ BUN, ↑ kidney wt, enlargement of kidney, pallor, pelvic dilatation,

thickened capsule in kidney, granular appearance to the kidney surface,

kidney cysts, dilatation of the ureters.

7000 ppm (with sRBC): ↓ thymus wt.

28-Day Immunotoxicity

(dietary)

CD-1 Mouse

PMRA #2704593

NOAEL = 5000 ppm (1139 mg/kg bw/day)

≥1000 ppm (228 mg/kg bw/day): ↑ rel liver wt.

≥2000 ppm (449 mg/kg bw/day): ↑ abs liver wt.

5000 ppm (1139 mg/kg bw/day): ↓ bwg.

Uterotrophic Assay

(gavage for 3 days)

Sprague Dawley Juvenile ♀

Rat

PMRA #2704584

≥500 mg/kg bw/day: rel liver wt.

1000 mg/kg bw/day: ↓ bw, ↓ bwg, ↑ abs liver wt, ↑ rel kidney wt.

No treatment-related effects on uterine wt; positive controls demonstrated

expected results.

Hershberger Assay

(gavage for 10 days)

Sprague Dawley ♂ Rat

PMRA #2704597

1000 mg/kg bw/day: sporadic occurrences of stained anus and soft stools, ↓

bwg in anti-androgen assay only, ↑ liver wt, ↑ kidney wt.

No treatment-related effects on accessory sex organ wts; positive controls

demonstrated expected results.

Negative for androgenicity and anti-androgenicity.

Pubertal Development and

Thyroid Function Assay in ♂

Sprague Dawley

Juvenile/Peripubertal ♂ Rat

PMRA #2704605

≥500 mg/kg bw/day: clear material around mouth post-dosing, ↑ liver wt, ↓

ventral prostate wt, dorsolateral prostate wt , ↑ serum urea nitrogen, ↓

testosterone, hepatocellular hypertrophy, ↑ severity of hepatocellular mitotic

figures, renal tubular dilatation and degeneration, ↓ incidence of renal

mononuclear infiltrate, ↑ incidence of slight reduction in thyroid colloid

area, ↑ slight increase in thyroid follicular cell height.

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 47

Study Type/

Animal/PMRA #

Study Results

1000 mg/kg bw/day: ↓ bw, ↓ bwg, delay for complete preputial separation,

two ♂ with small sex organs at necropsy, ↑ kidney wt, ↓ seminal vesicle wt,

↓ LABC wt, ↓ epididymis wt, ↓ testis wt, ↓ incidence of renal basophilic

tubules, renal mineralization.

No effect on serum T4, TSH.

Pubertal Development and

Thyroid Function Assay in ♀

(gavage for 20 days)

Sprague Dawley

Juvenile/Peripubertal ♀ Rat

PMRA #2704602

≥500 mg/kg bw/day: one mortality, ↑ liver wt, ↑ kidney wt, hepatocellular

hypertrophy and mitotic figures, renal tubular degeneration and/or dilatation,

↓ incidence of renal mononuclear infiltrate.

1000 mg/kg bw/day: ↓ bw, ↓ bwg, delay for incomplete vaginal opening, ↓

♀ cycling regularly, ↑ BUN, slight ↑ TSH, ↓ ovary wt, ↓ incidence of renal

basophilic tubules.

No effect on complete vaginal opening time, day of first estrus, estrous cycle

length, number of animals cycling, pathology of ovary, uterus or thyroid,

thyroid wt or serum T4.

Testosterone and Thyroid

Gland Mechanistic Study

(gavage for 30 days)

Sprague Dawley

Juvenile/Peripubertal ♂ Rat

PMRA #2704604

≥500 mg/kg bw/day: ↓ bw, ↓ bwg, delay in complete preputial separation, ↑

cholesterol, ↓ triglycerides, ↑ serum urea nitrogen, ↑hepatic enzymes

CYP2b, CYP4A, UGT, CYP3A, ↓ testosterone, ↑ rel liver wt, ↑ rel kidney

wt, ↓ abs LABC wt, hepatocellular hypertrophy, proliferation of smooth

endoplasmic reticulum, ↑ severity of focal basophilic renal tubules, renal

tubular degeneration, necrosis and dilatation, renal mineralization, ↓ colloid

area in thyroid, ↑ thyroid follicular cell height.

1000 mg/kg bw/day: one death (enlarged adrenal and testis and small

thymus at necropsy), ↓T4, ↓ rel LABC wt, ↓ abs epididymides wt, slight

renal papillary edema.

No effect on 17β-hydroxysteroid dehydrogenase activity in the testis.

Positive controls showed induction of hepatic microsomal enzymes

(CYP2B, CYP4A, UGT, CYP3A with phenobarbital, CYP4A with DEHP),

↑ liver wt, hepatocellular hypertrophy, reduced thyroid colloid area, ↑

thyroid follicular cell height; phenobarbital also had ↓T3, ↑TSH and slightly

↓ testosterone. Positive controls did not demonstrate anti-androgenic activity

at dose level tested.

In vitro Aromatase Inhibition

Assay

Human recombinant

aromatase (CYP19)

microsomes

PMRA #2704598

No inhibition of aromatase activity.

In vitro Androgen Receptor

Binding Assay

Ventral prostate cytosol from

Sprague Dawley rat

PMRA #2704599

No effect on specific binding of ligand in competitive binding experiment,

thus considered a non-binder.

In vitro Steroidogenesis

Assay

Precipitation at 100 μM and cytotoxicity at 30 μM

No effect on testosterone production up to 10 μM

Appendix II

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Page 48

Study Type/

Animal/PMRA #

Study Results

H295R human

adrenocortical carcinoma

cells

PMRA #2704600

↑ estradiol production (1.7-1.8-fold) at 10 μM.

In vitro Estrogen Receptor

Binding Assay

Uterine cytosol from

Sprague Dawley rat

PMRA #2704601

No effect on specific binding of ligand in competitive binding experiment,

thus considered a non-binder.

ToxCast Studies

Cell-free high-throughput

assays

PMRA #2704603

Inhibition of radio-ligand binding was less than 50% for all concentrations

(0.02-50 μM ) for bovine and human estrogen receptors, bovine and human

progesterone receptors, rat and human androgen receptors and human

thyroid receptor-α.

Inhibition of human aromatase enzyme activity less than 50% for all

concentrations (0.009-20 μM).

ToxCast Studies

Cell-based high-throughput

assays

PMRA #2704603

Inactive for agonist activity at the human AR, human ER-α and the human

thyroid hormone receptor-β. Pyriproxyfen did not block (or antagonize) the

activity of established ligands at these receptor sites.

In vitro Estrogen Receptor

Transcriptional Activation

Assay

BG1 human ovarian

carcinoma cells

PMRA #2831625

of 2.9 × 10-5M

Weakly estrogenic.

In vitro Estrogenic Activity

mtT/Se rat pituitary tumour

cells

PMRA #2831627

of 5.5 × 10-5M

Weakly estrogenic.

In vitro Cytotoxic Response

(neutral red incorporation

assay)

Chinese hamster ovary K1

cells

PMRA #2831624

Pyriproxyfen showed increased cytotoxicity with time – NRI

values were

377, 83 and 59 μM following 24, 48 and 72 hrs incubation resp. The

inclusion of fetal calf serum or bovine serum albumin diminished the

cytotoxicity suggesting protein binding. Pre-incubation of pyriproxyfen with

0, 4, 10 or 30% S9 fraction for 24 hrs also diminished the cytotoxicity

suggesting that the phase I metabolites were less toxic than pyriproxyfen.

In vitro Hepatotoxic

Response (MTT assay)

Hepatoma HepG2 cells

PMRA #2831626

Pyriproxyfen was cytotoxic at all concentrations (cell viability

approximately 50% at 1-10 ppm and <10% at 100 ppm) with both 24 and 48

hr incubation in MTT assay. Intracellular lipids were increased at ≥ 1 ppm

(using oil-red-O staining).

Appendix II

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Page 49

Study Type/

Animal/PMRA #

Study Results

Pyriproxyfen Metabolite Studies

Acute Oral Toxicity

4'-OH-pyr

5"-OH-pyr

DPH-pyr

POPA

PYPAC

CD-1 mouse

PMRA #2704568

>2000 mg/kg bw (methylcellulose) for all metabolites tested

≥1000 mg/kg bw:

5"-OH-pyr: ↓ spontaneous activity.

2000 mg/kg bw:

5"-OH-pyr: death in 1 out of 5 ♂, ataxic gait.

DPH-pyr: ↓ spontaneous activity, ataxic gait, prone position.

POPA: ↓ spontaneous activity, ataxic gait, prone position, lateral position,

irregular respiration.

PYPAC: ↓ spontaneous activity.

All clinical signs disappeared after 24 hrs.

Acute Oral Toxicity

2,5-OH-py

CD-1 mouse

PMRA #2704569

= 1150 mg/kg bw (♂), 1000 mg/kg bw (♀) (methyl cellulose)

≥250 mg/kg bw: ↓ spontaneous activity (♂).

≥500 mg/kg bw: ataxic gait, mortality in 1 animal after 4 days (♂); ↓

spontaneous activity (♀).

≥1000 mg/kg bw: prone position, irregular respiration, hypothermia,

mortality after 24 hrs (♂); ataxic gait, irregular respiration, mortality within

2-24 hrs (♀).

≥2000 mg/kg bw: mortality within 2-24 hrs (♂).

Acute Oral Toxicity

2-OH-py

CD-1 mouse

PMRA #2704570

= 124 mg/kg bw (♂), 166 mg/kg bw (♀) (distilled water)

≥50 mg/kg bw: ↓ spontaneous activity.

≥140 mg/kg bw: ataxic gait, irregular respiration; mortality in 4/5 animals

within 48 hrs (♂); mortality in 1 animal within 48 hrs (♀).

≥190 mg/kg bw: mortality in all animals within 24 hrs (♂); mortality in 4/5

animals within 72 hrs (♀).

≥270 mg/kg bw: mortality in all animals within 24 hrs (♀).

In vitro Bacterial Reverse

Mutation Assay

2,5-OH-py

Salmonella typhimurium

strains TA 98, TA 100, TA

1535, TA 1537 and TA

1538;

E. Coli WP2uvrA

PMRA #2704573

Negative with and without metabolic activation.

In vitro Bacterial Reverse

Negative with and without metabolic activation.

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 50

Study Type/

Animal/PMRA #

Study Results

Mutation Assay

4'-OH-pyr

5"-OH-pyr

DPH-pyr

POPA

PYPAC

Salmonella typhimurium

strains TA 98, TA 100, TA

1535, TA 1537 and TA

1538;

E. Coli WP2uvrA

PMRA #2704574

In vitro Bacterial Reverse

Mutation Assay

2-OH-py

Salmonella typhimurium

strains TA 98, TA 100, TA

1535, TA 1537 and TA

1538;

E. Coli WP2uvrA

PMRA #2704575

Negative with and without metabolic activation.

Table 3 Reference Values for Use in Human Health Risk Assessment for Pyriproxyfen

Exposure Scenario

Study

Point of Departure and Endpoint

CAF1 or

Target MOE

Acute dietary

Not required as no endpoint of concern attributable to a single exposure was

identified.

Repeated dietary

Mouse oncogenicity

NOAEL = 16 mg/kg bw/day

Reduced survival

100

ADI = 0.2 mg/kg bw/day

Short- and intermediate-

term dermal

2 and inhalation3

(adults)

Rabbit

developmental

toxicity

NOAEL = 100 mg/kg bw/day

Increased abortions/premature

deliveries

300

Short- and intermediate-

term dermal

2 and inhalation3

(children)

Rat developmental

toxicity

NOAEL = 100 mg/kg bw/day

Reduced pup weight and equivocal

decrease in pup viability

100

Long-term dermal2 and

inhalation

Mouse oncogenicity

NOAEL = 16 mg/kg bw/day

Reduced survival

100

Non-dietary oral ingestion

(short-term)

90-Day rat toxicity

NOAEL = 24 mg/kg bw/day

Effects on liver and hematology

100

Short- and intermediate

term aggregate (adults)

Rabbit

developmental

toxicity

NOAEL = 100 mg/kg bw/day

Increased abortions/premature

deliveries

300

Appendix II

Proposed Re-evaluation Decision - PRVD2019-10

Page 51

Exposure Scenario

Study

Point of Departure and Endpoint

CAF1 or

Target MOE

Short- and intermediate

term aggregate (children)

Rat developmental

toxicity

NOAEL = 100 mg/kg bw/day

Reduced pup weight and equivocal

decrease in pup viability

100

Long-term aggregate

Mouse oncogenicity

NOAEL = 16 mg/kg bw/day

Reduced survival

100

Cancer

No evidence of carcinogenicity in mice or rats. A cancer risk assessment is

not required.

1 CAF (composite assessment factor) refers to a total of uncertainty and PCPA factors for dietary

assessments; MOE refers to a target MOE for occupational and residential assessments

2 Since an oral NOAEL was selected, a dermal absorption factor was used in a route-to-route extrapolation

Since an oral NOAEL was selected, an inhalation absorption factor of 100% (default value) was used in route-to-

route extrapolation.

Appendix III

Proposed Re-evaluation Decision - PRVD2019-10

Page 52

Appendix III Dietary Exposure and Risk Assessments

Summary of Dietary Exposure and Risk from Pyriproxyfen

Population Subgroup Chronic Dietary1 (Food Only)

Exposure (mg/kg bw/day) %ADI

General Population 0.009679 4.8

All Infants (<1 year old) 0.014614 7.3

Children 1-2 years old 0.025863 12.9

Children 3-5 years old 0.022463 11.2

Children 6-12 years old 0.014221 7.1

Youth 13-19 years old 0.008737 4.4

Adults 20-49 years old 0.008184 4.1

Adults 50-99 years old 0.007215 3.6

Females 13-49 years old 0.007887 3.9

1 Acceptable Daily Intake (ADI) of 0.2 mg/kg bw/day applies to the general population and all population

subgroups.

Appendix III

Proposed Re-evaluation Decision - PRVD2019-10

Page 53

Food Residue Chemistry Summary

Currently registered food uses of pyriproxyfen in Canada are greenhouse uses on tomato, pepper,

cucumber and eggplant. In addition, some products containing pyriproxyfen (for example,

NYLAR®) are registered for space, general surface, spot, and/or crack and crevice treatment,

provided that exposed food is covered or removed from the area being treated prior to

application.

The first comprehensive dietary risk assessment for pyriproxyfen was conducted in support of the

Proposed Registration Decision Document PRDD2006-04, Pyriproxyfen, published on

12 September 2006 for greenhouse use on tomato, cucumber and pepper. The assessment was

updated in 2011 for the use expansion to greenhouse eggplant. Further updates were conducted in

2013 and 2015 in support of the establishment of MRLs on various imported commodities.

The residue chemistry database for pyriproxyfen is complete and up-to-date for the registered

uses. The residue definition in plant and animal commodities was previously determined to be

pyriproxyfen per se for enforcement and risk assessment purposes. No change is being proposed

as a result of this re-evaluation. This residue definition is aligned with current residue definitions

established by the United States Environmental Protection Agency (USEPA), the European Food

Safety Authority (EFSA) and JMPR/Codex. It should be noted that, in addition to parent

pyriproxyfen, the USEPA has included the free and sulfate forms of the metabolite 4-OH-pyr in

its residue definition for animal commodities. However, USEPA concluded that there is no

expectation of finite residues in animal commodities and, therefore, waived the necessity of

establishing tolerances in animal commodities. There are currently no Canadian registrations on

major livestock feed items.

A gas chromatography with nitrogen-phosphorus detection (GC/NPD) method is available for

enforcement of pyriproxyfen MRLs. The limit of detection (LOD) and limit of quantitation

(LOQ) are 0.01 and 0.02 ppm, respectively. In addition, pyriproxyfen is included in the scopes of

multiresidue analytical methods used by the Canadian Food Inspection Agency (CFIA) and the

United States Department of Agriculture Pesticide Data Program (USDA PDP).

Appendix IV

Proposed Re-evaluation Decision - PRVD2019-10

Page 54

Appendix IV Occupational Mixer/Loader/Applicator and Postapplication Risk Assessment

Table 1 Occupational Mixer/Loader/Applicator Exposure and Risk Assessment

Scenarioa Application

Equipment Application

Rateb ATPDc

Exposured

(mg/kg bw/day)

MOE

Dermal

Inhalation

Combined

Dermale

Inhalationf

Combined

Mixer/Loader/Applicator: Single Layer, CR gloves

Indoor Structures

(crack & crevice, spot,

broadcast)

(T = 300)

MPHW 0.16 g a.i./L 40 L 6.9 × 10-3 2.6 × 10-5 6.9 × 10-3 14600 3810000 14500

Greenhouse

Ornamentals,

Tomatoes, Cucumbers,

Peppers, Eggplants

(T = 100)

MPHG 0.0464 g

a.i./Lg

3800 L 1.2 × 10-2 3.3 × 10

-4

1.3 × 10

-2

8100 300500 7900

MPHW

150 L

8.2 × 10-5

3.9 × 10-6

8.6 × 10-5

1218400 25429800 1162700

Backpack 4.7 × 10-4 1.3 × 10

-5

5.4 × 10-6 211100 18509300 208700

ATPD = Volume treated or handled per day; MOE = Margin of Exposure; Single layer = long-sleeved shirt, long pants; MPHG = Mechanically Pressurized Handgun; MPHW =

Manually-Pressurized Hand wand; T = Target MOE; CR = chemical-resistant

a The application method or scenario where the application equipment may be used.

b Maximum application rates were used for each scenario/application equipment.

c Volume treated or handled per day values.

d Exposure = Unit Exposure (µg/kg a.i.) × ATPD × Application Rate × dermal absorption (100%) / Body Weight (80 kg). Unit exposure values from PHED or Krolski, 2014.

e Dermal MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity

study.

f Inhalation MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity

study.

g Application rate to greenhouse ornamentals is 29.7 g a.i./ha, but only highest rate to all greenhouse crops (92.8 g a.i./ha) was shown in this risk assessment.

Table 2 Occupational Postapplication Exposure and Risk Assessment

Use(s) Ratea

(g/ha) NAPS Interval

(days) Activityb TC

(cm2/hr)

DFRc Inputs

Day 0 Dermal Estimatesf

REI

(days)

Peak Disp DFR0f

Exposured (µg/kg

bw/day)

MOEe

Cut Flowers 29. 7 4 14

Pruning,

Disbudding, Hand

Harvesting

4000 25% 2.3% 0.19 77.8 200 0.5

Appendix IV

Proposed Re-evaluation Decision - PRVD2019-10

Page 55

Use(s) Ratea

(g/ha) NAPS Interval

(days) Activityb TC

(cm2/hr)

DFRc Inputs

Day 0 Dermal Estimatesf

REI

(days)

Peak Disp DFR0f

Exposured (µg/kg

bw/day) MOEe

GH Ornamentals

(Non-cut flowers)

All activities

230 4.47 3580

GH tomatoes,

peppers,

cucumbers,

eggplants

92.8 1400 0% 0.93 130 120

NAPS = Number of Applications per Season, TC = Transfer Coefficient, DFR = Dislodgeable Foliar Residue, Peak = Peak DFR as Percent of Application Rate, Disp = Percent

Dissipation per Day, DFR0 = Day 0 DFR (ug/cm2), MOE = Margin of Exposure, REI = Restricted-Entry Interval, GH = Greenhouse

a Maximum application rates were used.

b Activity with the highest TC for each crop was included in this table.

c The default peak DFR value of 25% of the application rate was assumed and a dissipation rate of 2.3%/day was assumed for greenhouse ornamental scenarios, a dissipation rate

of 0%/day was assumed for greenhouse vegetable scenarios

d Dermal exposure on Day 0 after application = TC × DFR × 8 hours/day × Dermal Absorption (100%) / Body Weight (80 kg).

e Dermal MOEs for long-term exposure scenarios are based on a NOAEL of 16 mg/kg bw/day (target MOE is 100) from an oral mouse oncogenicity study.

f Calculated for day 0 after the last application.

Appendix V

Proposed Re-evaluation Decision - PRVD2019-10

Page 56

Appendix V Residential Applicator and Postapplication Risk Assessment

Table 1 Residential Applicator Exposure and Risk Assessment

Scenarioa Application Rateb ATPD/Amount

Handled per Dayc

Absorbed Dose (mg/kg bw/day)d

MOE (T = 300)

Dermal Inhalation Dermale Inhalationf Combined

Spot, crack and crevice

(Pressurized product can)

0.000075 kg

a.i./can 0.5 can 0.0003824 0.0000031 260000 32000000 260000

Spot, crack and crevice

(trigger spray bottle)

0.000088 kg

a.i./can

0.5 bottle

0.0001032

7.15 × 10-8

1100000

1500000000

1100000

Broadcast (trigger spray

bottle)

1 bottle

0.0002063

1.43 × 10-5

530000

760000000

530000

Treated pets (shampoo)

0.0001995 kg

a.i./pet 2 pets

0.0219911 0.0000032 4500 31000000 4500

Treated pets (spot-on)g

0.0000976 kg

a.i./pet 0.0006455 NA 150000 NA NA

ATPD = Area Treated Per Day; MOE = Margin of Exposure; T = Target MOE; NA = Not Applicable

a The application method or scenario where the application equipment may be used.

b Maximum rates were used for each scenario/application equipment.

c Volume treated or handled per day values.

d Absorbed Dose = Unit Exposure (µg/kg a.i.) × ATPD × Application Rate × Dermal Absorption (100%) / Body Weight (80 kg). Unit exposure values from USEPA, 2012.

e Dermal MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity study.

f Inhalation MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity study.

g Applicator was wearing gloves in the study used to determine exposure for this scenario. Inhalation exposure is considered to be negligible for spot-on applications (USEPA, 2012).

Table 2 Residential Postapplication Dermal Exposure and Risk Assessment

Exposure Scenario Lifestage

TR a

(µg/cm

)

TC b

(cm

/hr)

ET c

(hr/day)

Dermal Dose d

(mg/kg bw/day)

MOE e

Applied by commercial applicator

Indoor

Environments

Broadcast Soft surface

Adult

0.0288

6800

0.01958

5100

Children 1<2

1800

0.01885

5300

Hard surface

Adult

0.0384

6800

0.00653

15000

Children 1<2

1800

0.01257

8000

Perimeter/Spot Soft surface

Adult

0.0144

6800

0.00979

10000

Children 1<2 1800 4 0.00943 11000

Hard surface

Adult

0.0192

6800

0.00326

31000

Appendix V

Proposed Re-evaluation Decision - PRVD2019-10

Page 57

Exposure Scenario Lifestage

TR a

(µg/cm

)

TC b

(cm

/hr)

ET c

(hr/day)

Dermal Dose d

(mg/kg bw/day)

MOE e

Children 1<2

1800

0.00628

16000

Crack and crevice Soft surface

Adult

0.0029

6800

0.00196

51000

Children 1<2

1800

0.00189

53000

Hard surface

Adult

0.0038

6800

0.00065

150000

Children 1<2

1800

0.00126

80000

Applied by residential applicator

Indoor

Environments

Broadcastf

(Trigger pump

sprayer)

Soft surface

Adult

0.0372

6800

0.02530

4000

Children 1<2

1800

0.02435

4100

Hard surface

Adult

0.0496

6800

0.00843

12000

Children 1<2

1800

0.01623

6200

Perimeter/Spot

(Pressurized Product)

Soft surface

Adult

0.750

1800

0.01338

7500

Children 1<2

6800

0.01288

7800

Hard surface

Adult

1.000

1800

0.00446

22000

Children 1<2

6800

0.00859

12000

Treated Pets

Shampoo (dog)

Small

Adult

0.0013

5200

0.77

0.07

1500

Children 1<2

1400

0.17

590

Medium

Adult

0.0006

5200

0.77

0.03

3500

Children 1<2

1400

0.07

1400

Large

Adult

0.0004

5200

0.77

0.02

5500

Children 1<2

1400

0.05

2200

Spot-on (dog)

Small

Adult

0.0007

5200

0.77

0.03257

3100

Children 1<2

1400

0.08281

1200

Medium

Adult

0.0003

5200

0.77

0.01396

7200

Children 1<2

1400

0.03549

2800

Large

Adult

0.0002

5200

0.77

0.00888

11000

Children 1<2

1400

0.02259

4400

Spot-on (cat)

Small

Adult

0.0005

5200

0.77

0.02289

4400

Children 1<2

1400

0.05821

1700

Medium

Adult

0.0003

5200

0.77

0.01373

7300

Children 1<2

1400

0.03492

2900

Large

Adult

0.0002

5200

0.77

0.00858

12000

Children 1<2

1400

0.02183

4600

TR = Transferable residue; TC = Transfer coefficient; ET = Exposure time; MOE = Margin of exposure

a Transferable residues calculated based on the application rate and the exposure scenario using default fraction transferred values of 2% for pets, 6% for soft surfaces and 8% for hard surfaces

(USEPA, 2012). Maximum application rates were used.

b Transfer coefficient default values from the USEPA Residential SOPs (USEPA, 2012) were used .

c Exposure time default values from the Residential SOPs (USEPA, 2012) were used.

d Dermal dose = TR × TC × ET/BW (kg) Body weights of 80 and 11 kg were used for adults and children (1 <2 years) respectively, as stated in the USEPA Residential SOPs (USEPA, 2012). Dermal

absorption was assumed to be 100%.

e MOE = NOAEL/ exposure, based on a NOAEL of 100 mg/kg bw/day from an oral rabbit developmental toxicity study and a target MOE of 300 for adults, and a NOAEL of 100 mg/kg bw day from

an oral rat developmental toxicity study and a target MOE of 100 for children, applicable to short- to intermediate-term exposure scenarios.

f Broadcast application is expected to result in higher exposure relative to perimeter/spot application, therefore only broadcast application of trigger pump sprayer product is presented

Appendix V

Proposed Re-evaluation Decision - PRVD2019-10

Page 58

Table 3 Residential Postapplication Incidental Oral Exposure and Risk Assessment for Children (1<2 Years old)

Exposure Scenario

Hand Residue (mg/hour) or Object

Residue (µg/cm

)

ETb

(hr/day)

Oral Dosec

(mg/kg bw/day)

Incidental Oral MOEd

Applied by commercial applicator

Indoor Environments

HtM Broadcast

Soft surface

0.0039

0.00018

140000

Hard surface

0.0052

0.00012

200000

HtM Perimeter/Spot

Soft surface

0.0019

0.00009

270000

Hard surface

0.0026

0.00006

410000

HtM Crack and Crevice

Soft surface

0.0004

0.00002

1400000

Hard surface

0.0005

0.00001

2000000

OtM Broadcast

Soft surface

0.0288

0.00038

64000

Hard surface

0.0384

0.00025

96000

OtM Perimeter/Spot

Soft surface

0.0144

0.00019

130000

Hard surface

0.0192

0.00013

190000

OtM Crack and Crevice

Soft surface

0.0029

0.00004

640000

Hard surface

0.0038

0.00003

960000

Applied by residential applicator

Indoor Environments

HtM Broadcast

(Trigger pump sprayer)

Soft surface

0.0050

0.00023

110000

Hard surface

0.0067

0.00015

160000

HtM Perimeter/Spot

(Pressurized Product)

Soft surface

0.1013

0.00012

200000

Hard surface

0.1350

0.00008

300000

OtM Broadcast

(Trigger pump sprayer)

Soft surface

0.0372

0.00049

49000

Hard surface

0.0496

0.00032

74000

OtM Perimeter/Spot

(Pressurized Product)

Soft surface

0.7500

0.00026

93000

Hard surface

1.0000

0.00017

140000

Treated Pets

HtM Shampoo (dog)

Small

0.0372

0.00042

57000

Medium

0.0160

0.00018

130000

Large

0.0102

0.00012

210000

HtM Spot-on (dog)

Small

0.0182

0.00021

120000

Medium

0.0078

0.00009

270000

Large

0.0050

0.00006

420000

HtM Spot-on (cat)

Small

0.0128

0.00015

160000

Medium

0.0077

0.00009

270000

Large

0.0048

0.00005

440000

ET = Exposure time; MOE = Margin of exposure; HtM = Hand-to-Mouth; OtM = Object-to-Mouth

a Based on the dermal postapplication exposure from indoor applications without the body weight × fraction of a.i. on hands compared to the body (0.15)/(4 hr × 4 intervals/hr).

b Exposure time based on default values from the USEPA (USEPA, 2012).

c Oral dose = [Hand Residue (mg/cm2) × (Fraction of hand mouthed/event (0.13) × Surface Area of one hand (150 cm2)) × (Exposure Time (hr) × Replenishment Intervals (4/hr)) × (1 – (1 – Saliva

Extraction Factor (0.48)) Number events per hour (20)/Replenishment Intervals (4/hr))]/ Body Weight (11 kg) or oral dose = Object Residue (µg/cm2) × Conversion factor (mg/µg) × Surface area of object mouthed (10

cm2/event) × [Exposure time (hrs) × Number of replenishments per hour (4)] × [1-(1-Saliva Extraction Factor (0.48))Frequency of OtM contacts per hour (14)/Number of replenishments per hour (4)] / Body Weight (11 kg)

d MOE = NOAEL / exposure, based on a NOAEL of 24 mg/kg bw/day from a 90-day oral rat toxicity study and a target MOE of 100 for children, applicable to short-term exposure scenarios.

Appendix VI

Proposed Re-evaluation Decision - PRVD2019-XX

Page 59

Appendix VI Aggregate Risk Assessment

Table 1 Aggregate Exposure and Risk Assessment

Scenario Lifestage

Dermal

Exposurea

(mg/kg

bw/day)

Inhalation

Exposureb (mg/kg

bw/day)

Incidental Oral

Exposurec,d

(mg/kg bw/day)

Chronic Dietary

Exposuree (mg/kg

bw/day)

Aggregate

MOEf

Indoor Environments

(Commercially applied

Broadcast)

Soft surfaces

Adult

0.01958

0.007822

3650

Children (1< 2 yrs)

0.01885

0.00038

0.025864

2220

Hard surfaces

Adult

0.00653

0.007822

6970

Children (1< 2 yrs)

0.01257

0.00025

0.025864

2590

Indoor Environments

(Domestically applied

Perimeter/Spot with

pressurized product)

Soft surfaces

Adult

0.01376

3.10 × 10-6

0.007822

4630

Children (1< 2 yrs)

0.01288

0.00026

0.025864

2560

Hard surfaces

Adult

0.00484

3.10 × 10-6

0.007822

7890

Children (1< 2 yrs)

0.00859

0.00017

0.025864

2890

Indoor Environments

(Domestically applied

Broadcastg with trigger

pump sprayer)

Soft surfaces

Adult

0.02549

1.00 × 10-7

0.007822

3000

Children (1< 2 yrs)

0.02435

0.00049

0.025864

1970

Hard surfaces

Adult

0.00862

1.00 × 10-7

0.007822

6080

Children (1< 2 yrs)

0.01623

0.00032

0.025864

2360

Treated Pets

(shampoo)

Adult

0.08856

3.19 × 10-6

0.007822

1040

Children (1< 2 yrs)

0.16927

0.00042

0.025864

510

Treated Pets

(spot-on)

Adult

0.03321

0.007822

2440

Children (1< 2 yrs)

0.08281

0.00021

0.025864

920

NA = Not Applicable; MOE = Margin of Exposure; yrs = years

a Combined dermal exposure resulting from application (when applicable) and postapplication exposure.

b Inhalation exposure resulting from application exposure, when applicable.

c Incidental oral exposure reflects either hand-to-mouth exposure for treated pets or object-to-mouth exposure for indoor environments. Incidental oral exposure is only applicable to children 1 <2 years

old.

d Treated indoor environments may result in both hand-to-mouth and object-to-mouth exposure. Since object-to-mouth exposure is higher, object-to-mouth exposure was aggregated.

e Chronic dietary exposure (food only) is based on information provided in the dietary risk assessment.

f Aggregate MOE = Aggregate NOAEL/Aggregate Exposure (dermal+inhalation+incidental oral+dietary), based on an aggregate NOAEL of 100 mg/kg bw/day from an oral rabbit developmental

toxicity study and a target MOE of 300 for adults, and an aggregate NOAEL of 100 mg/kg bw day from an oral rat developmental toxicity study and a target MOE of 100 for children (1<2 years).

g Broadcast application is expected to result in higher exposure relative to perimeter/spot application, therefore only broadcast application of trigger pump sprayer product is presented.

Appendix VII

Proposed Re-evaluation Decision - PRVD2019-10

Page 60

Appendix VII Label Amendments for Products Containing Pyriproxyfen

The label amendments presented below do not include all label requirements for individual end-

use products, such as first aid statements, disposal statements, precautionary statements and

supplementary protective equipment. Information on labels of currently registered products

should not be removed unless it contradicts the label statements provided below.

I. For Technical Grade of the Active Ingredient and Manufacturing

Concentrate:

The following must appear under a section titled “ENVIRONMENTAL

PRECAUTIONS”:

“TOXIC to aquatic organisms.”

“DO NOT discharge effluent containing this product into sewer systems, lakes, streams,

ponds, estuaries, oceans or other waters.”

II. For Commercial End-Use Products for Greenhouse Uses:

1) Remove the following under the "PRECAUTIONS" section:

“This product contains a petroleum distillate which is moderately to highly toxic to

aquatic organisms. Avoid contamination of aquatic systems during application. Do not

contaminate these systems through direct application, disposal of waste or cleaning of

equipment.”

2) Under the section “ENVIRONMENTAL HAZARDS”, remove the following:

“This pesticide is toxic to fish and aquatic invertebrates. Do not apply directly to water, or to

areas where surface water is present.”

And replace with the following:

“This product contains an active ingredient and aromatic petroleum distillates which are toxic to

aquatic organisms.”

3) Change the heading “ENVIRONMENTAL HAZARDS” to “ENVIRONMENTAL

PRECAUTIONS”

4) Under “DIRECTIONS FOR USE: MIXING INSTRUCTIONS (Booklet label)”:

Add:

"As this product is not registered for the control of pests in aquatic systems, DO NOT use

to control aquatic pests."

Appendix VII

Proposed Re-evaluation Decision - PRVD2019-10

Page 61

“DO NOT contaminate irrigation or drinking water supplies or aquatic habitats by

cleaning of equipment or disposal of wastes.”

III. COMMERCIAL-CLASS PRODUCTS (with specific Registration Numbers)

1) For the label with the greenhouse uses (Registration Number 28414):

• Statements related to the personal protective equipment (PPE) and restricted-entry

interval (REI) are proposed to be updated to current wording.

o For PPE, replace:

“Wear coveralls or long-sleeved shirt and long pants, rubber boots, goggles,

gloves (rubber, PVC, neoprene or nitrile) and hat during mixing, loading, cleanup

and application.”

with:

“Wear a long-sleeved shirt, long pants, chemical-resistant gloves (rubber, PVC,

neoprene or nitrile), socks and shoes during mixing, loading, application, clean-up

and repair.”

o For REI, replace:

“DO NOT re-enter treated areas within 12 hours.”

with:

“DO NOT enter or allow worker entry into treated areas during the restricted

entry interval (REI) of 12 hours.”

• Statements are proposed to prohibit application using handheld mist blower or handheld

fogging equipment, as data are not available to assess these uses.

• Add to Directions For Use: “Do not apply greenhouse processing water containing this

product to field crops (food and feed).”

2) For the label with directions to control fleas in indoor environments (Registration

Number 25490):

• The following PPE as per the occupational risk assessment are proposed to be added to

the label:

“Wear a long-sleeved shirt, long pants, chemical-resistant gloves, socks and shoes

during mixing, loading, application, clean-up and repair.”

• Statements related to entry after application are proposed to be updated to current

wording as follows:

“BROADCAST APPLICATION: DO NOT allow people or pets to enter treated

areas for 2 hours or until sprays have dried.

SPOT AND CRACK AND CREVICE APPLICATION: DO NOT allow people or

Appendix VII

Proposed Re-evaluation Decision - PRVD2019-10

Page 62

pets to enter treated areas until sprays have dried.”

• Best practice statements to update the precautionary label directions as per PRO2018-04

are proposed:

Under “DIRECTIONS FOR USE”:

“DO NOT apply to mattresses, linens, toys or clothing.”

“DO NOT apply to overhead areas or in confined spaces without appropriate

respiratory and eye protection.”

“DO NOT allow spray to drip or allow drift onto non-target surfaces; any spray

residue on non-target areas must be removed by the applicator.”

“DO NOT apply as a space spray.”

“Use a coarse, low pressure spray not exceeding 345 kPa (50 psi).”

Under “PRECAUTIONS”:

“DO NOT apply to surfaces that may come into contact with food/feed.”

“Cover or remove all food/feed. Cover all food/feed processing surfaces,

equipment and utensils or thoroughly wash following treatment.”

“Ventilate treated areas after application either by opening windows and doors or

through use of air exchange/ventilation systems confirmed to be operational. Use

fans where required to aid in the circulation of air.”

“DO NOT apply when people or pets are present.”

IV. DOMESTIC-CLASS PRODUCTS

End-use products with instructions for indoor applications to control fleas and which are co-

formulated with tetramethrin or d-phenothrin have conflicting application directions as a result of

label changes required for the re-evaluation of tetramethrin or d-phenothrin. Therefore, label

changes are proposed to clarify application directions for specific use sites while ensuring

consistency with the evaluations of tetramethrin and d-phenothrin.

These label amendments include:

• Removal of label statements restricting application to crack and crevice and perimeter

applications. Directions for spot treatment are proposed to remain for products co-

formulated with tetramethrin.

• Application directions, including clarification of rates, are proposed to be added for

specific uses on the current labels, that is, for pet bedding, indoor surfaces (rugs, carpets

and drapes) and upholstery.

• In addition, best practice statements to update the precautionary label directions as per

PRO2018-04 are proposed:

Under “DIRECTIONS FOR USE”:

Appendix VII

Proposed Re-evaluation Decision - PRVD2019-10

Page 63

“DO NOT apply to mattresses, linens, toys or clothing.”

“DO NOT apply to overhead areas or in confined spaces without appropriate respiratory

and eye protection.”

“DO NOT allow spray to drip or allow drift onto non-target surfaces; any spray residue

on non-target areas must be removed by the applicator.”

“DO NOT apply as a space spray.”

“Use a coarse, low pressure spray not exceeding 345 kPa (50 psi).”

Under “PRECAUTIONS”:

“DO NOT apply to surfaces that may come into contact with food/feed.”

“Cover or remove all food/feed. Cover all food/feed processing surfaces, equipment and

utensils or thoroughly wash following treatment.”

“Ventilate treated areas after application either by opening windows and doors or through

use of air exchange/ventilation systems confirmed to be operational. Use fans where

required to aid in the circulation of air.”

“DO NOT apply when people or pets are present.”

“DO NOT allow people or pets to enter treated areas [“until sprays have dried” or re-

entry time currently stated on label].”

• Remove from all domestic-class indoor application labels:

“[Retreat/Repeat] as necessary.”

For spot-on, pyriproxyfen products registered for use on cats and dogs, the following

precautionary label directions as per PRO2018-01 are proposed:

• For products used on dogs:

“Monitor your dog after application. Side effects may include: skin irritation such as

redness or scratching; changes in behaviour such as agitation or lethargy; or

gastrointestinal effects such as vomiting or loss of appetite. If these or other side effects

occur consult your veterinarian or [Registrant at 1-800-number].”

• For products used on cats:

“Monitor your cat after application. Side effects may include: skin irritation such as

scratching or hair loss at the application site, or changes in behaviour such as agitation or

lethargy. Gastrointestinal effects such as drooling, vomiting, or loss of appetite may also

occur. If these or other side effects occur consult your veterinarian or [Registrant at 1-

800-number].”

The following label improvements for spot-on products are proposed:

• Remove label language that allows re-application of the product before the end of the

effective control period. For example, products that are labeled as providing four weeks

of control, should not have statements such as “Reapply after one week if necessary”.

Appendix VII

Proposed Re-evaluation Decision - PRVD2019-10

Page 64

• Add label language to contraindicate use of other flea control products with the same

active ingredients as the spot-on (For example: “This product contains [name of active

ingredient(s)]. Do not apply another pest control product such as a shampoo, collar, or

powder which contains [name of active ingredient(s)] to the treated animal when using

[name of spot-on product]”).

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 65

References

Information Considered in the Chemistry Assessment

A. Studies/Information Submitted by Registrant

PMRA

Document

Number

Reference

1854753

1987, [CBI removed] Supplemental Volume 4 Response to Ag Canada Pesticides

Directorate Review Comments Product Chemistry Data - Ultraviolet-Visible

Absorption Spectra Determination of Sumilarv, DACO: 2.14.12 CBI

1854760

1989, [CBI removed] Sumilarv - Product Identity and Composition, DACO:

2.11.2,2.11.3,2.11.4 CBI

1854801

1989, [CBI removed] Sumilarv - Physical and Chemical Characteristics, DACO:

2.14.1,2.14.10,2.14.11,2.14.12,2.14.13,2.14.14,2.14.2,2.14.3,2.14.4,2.14.6,2.14.7,

2.14.9 CBI

1855168

1989, [CBI removed] Sumilarv - Product Identity and Composition (Revised) -

Product Identity, Description of Beginning Materials and Manufacturing Process,

Impurities, DACO: 2.11,2.14.1,2.14.13,2.14.2,2.14.4,2.3,2.5,2.6,2.7,2.8,2.9 CBI

2704557

2016, Batch Analysis of Pyriproxyfen Technical Grade, DACO: 2.13.3,2.13.4 CBI

Information Considered for the Toxicological Assessment

A. List of Studies/Information Submitted by Registrant

3.0 Human Health

PMRA

Document

Number

Reference

621875 1991, Mouse Micronucleus Test On S-31183, DACO: 4.5.7

1143882 1991, S31183: Toxicity Study by Oral (capsule) Administration to Beagle Dogs

for 52 weeks., DACO: 4.3.1,4.3.2

1143883 1998, Sumilarv-Subacute Inhalation Toxicity Study of S-31183 in Rats., DACO:

4.3.6

1143884 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND

ONCOGENICITY STUDY IN RATS WITH S-31183, DACO: 4.4.1,4.4.2

1143889 1987, SUMILARV-ACUTE ORAL TOXICITY OF S-31183 IN RATS, DACO:

4.2.1

1143893 1987, SUMILARV-ACUTE DERMAL TOXICITY OF S-31183 IN RATS,

DACO: 4.2.2

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 66

PMRA

Document

Number

Reference

1143894 1989, ACUTE INHALATION TOXICITY OF SUMILARV, DACO: 4.2.3

1143896 1987, SUMILARV-PRIMARY EYE AND SKIN IRRITATION TESTS WITH S-

31183 IN RABBITS, DACO: 4.2.4,4.2.5

1143897 1987, SUMILARV- SKIN SENSITIZATION TEST WITH S-31183 IN GUINEA

PIGS, DACO: 4.2.6

1143898 1988, SUMILARV- THREE MONTH ORAL TOXICITY STUDY OF S-31183

IN DOGS, DACO: 4.3.1,4.3.2

1143899 1989, SUMILARV- SUBCHRONIC TOXICITY STUDY WITH S-31183 IN

RATS, DACO: 4.3.1

1143902 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND

ONCOGENICITY STUDY IN RATS WITH S-31183 (343-214), DACO:

4.4.1,4.4.2

1143903 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND

ONCOGENICITY STUDY IN RATS WITH S-31183, DACO: 4.4.1,4.4.2

1143904 1991, A DIETARY 2-GENERATION (1 LITTER) REPRODUCTION STUDY

OF S-31183 IN THE RAT (CONT'D ON ROLL#1036), DACO: 4.5.1

1143905 1991, A DIETARY 2-GENERATION (1 LITTER) REPRODUCTION STUDY

OF S-31183 IN THE RAT, DACO: 4.5.1

1143906 1989, SUMILARV-STUDY OF S-31183 BY ORAL ADMINISTRATION

DURING THE PERIOD OF FETAL ORGANOGENESIS IN RABBITS (376),

DACO: 4.5.2

1143907 1988, SUMILARV-STUDY OF S-31183 BY ORAL ADMINISTRATION

DURING THE PERIOD OF FETAL ORGANOGENESIS IN RATS, DACO:

4.5.2

1143908 1989, SUMILARV-IN VITRO CHROMOSOMAL ABERRATION TEST OF

PYRIPROXYFEN IN CHINESE HAMSTER OVARY CELLS (CHO-K1),

DACO: 4.5.4

1143909 1988, SUMILARV- ASSESSMENT OF UNSCHEDULED DNA REPAIR

SYNTHESIS IN MAMMALIAN CELLS AFTER EXPOSURE TO S-31183,

DACO: 4.5.4

1143910 SUMILARV- REVERSE MUTATION TEST OF S-31183 IN BACTERIAL

SYSTEMS (153;NNT-80-0034), DACO: 4.5.4

1143911 1990, SUMILARV- IN VITRO GENE MUTATION TEST OF S-31183 IN V79

CHINESE HAMSTER CELLS, DACO: 4.5.4

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 67

PMRA

Document

Number

Reference

1143912 1991, SUMILARV-ONCOGENICITY STUDY IN MICE WITH S-31183 (343-

215), DACO: 4.4.2

1143930 1991, SUMILARV- ONCOGENICTITY STUDY IN MICE WITH S-31183,

DACO: 4.4.2

1143941 SUMILARV- METABOLISM OF S-31183 IN RATS (NNM-80-

0001;807;810;811), DACO: 4.5.9

1143949 1998, SUMILARV- METABOLISM OF S-31183 IN RATS (TISSUE

DISTRIBUTION STUDY), DACO: 4.5.9

1159013 ONCOGENICITY STUDY IN MICE (343-215,JULY 23,1991)(CRITERIA

UTLIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING

SYSTEM FOR HISTOPATHOLOGICAL LESIONS)(SUMILARV), DACO:

4.4.2

1159014 RABBIT TERATOLOGY STUDY (NNT-80-0003,AUGUST

30,1989)(ADDITIONAL DATA AND APPENDICES AS REQUESTED ON

VARIOUS POINTS SEE MICROFILM FOR EXACT DETAILS)(SUMILARV),

DACO: 4.5.2

1159015 RAT TERATOLOGY STUDY (NNT-80-0029,MARCH

28,1988)(ADDITIONAL DATA AS REQUESTED SEE MICROFILM FOR

MORE DETAIL)(SUMILARV), DACO: 4.5.2

1159016 METABOLISM STUDY IN RATS (NNM-80-0001,APRIL

14,1988)(ADDITIONAL DATA ON: NEW "QUALITY ASSURANCE

STATEMENT)(807,810,811)(SUMILARV), DACO: 4.5.9

1159046 1987, ACUTE ORAL TOXICITY IN RATS AMENDMENT TO FINAL

REPORT NO. NNT-70-0005, FEBRUARY 4, 1987 (INDIVIDUAL TOXIC

SIGNS/BODY WEIGHT/GROSS PATHOLOGY

FINDINGS)(ACT86033)(SUMILARV), DACO: 4.2.1

1159057 1987, ACUTE DERMAL TOXICITY IN RATS AMENDMENT TO FINAL

REPORT NO. NNT-70-0006,FEBRUARY 4,1987 (INDIVIDUAL BODY

WEIGHT/GROSS PATHOLOGY FINDINGS)(ACT86034)(SUMILARV),

DACO: 4.2.2

1159068 1994, ACUTE INHALATION TOXICITY IN RATS AMENDMENT TO FINAL

REPORT NO. NNT-70-0022,DECEMBER 3,1989 (PARTICLE

SIZE,INDIVIDUAL TOXIC SIGNS/BODY WEIGHT/GROSS PATHOLOGY

FINDINGS/INDIVIDUAL HISTOPATHOLOGICAL

EXAMINATION)(636)(SUMILARV), DACO: 4.2.3

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 68

PMRA

Document

Number

Reference

1159075 1994, SUBCHRONIC TOXICITY IN RATS (343-208)(ADDITIONAL

INDIVIDUAL ANIMAL ON OPHTHALMOSCOPIC

EXAMINATIONS)(SUMILARV), DACO: 4.3.1

1159076 1994, 52-WEEK TOXICITY IN DOGS (91/0776,AUGUST 1,1991)(CRITERIA

UTILIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING

SYSTEM FOR HISTOPATHOLOGICAL LESIONS)(SUMILARV), DACO:

4.4.1

1159077 1994, COMBINED CHRONIC TOXICITY AND ONCOGENICITY IN RATS

(343-214,SEPTEMBER 6,1991)(ADDITIONAL DATA ON: CRITERIA

UTILIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING

SYSTEM FOR HISTOPATHOLOGICAL LESIONS AND DATES OF

HISTORICAL CONTROL STUDIES)(SUMILARV) [contains a letter], DACO:

0.8,4.4.1,4.4.2

1164935 1994, SUMILARV- RESPONSE TO EPA REVIEW OF CHRONIC TOXICITY

AND/OR ONCOGENICITY STUDIES OF SUMILARV (S-31183) IN RATS

AND MICE., DACO: 4.4.1,4.4.2

1164978 1990, FINAL REPORT: SUMILARV-SUBCHRONIC TOXICITY STUDY IN

MICE., DACO: 4.3.1

1164979 1993, SUMILARV- 21 DAY DERMAL TOXICITY STUDY IN RATS WITH S-

31183., DACO: 4.3.4

1164980 1996, RESPONSE TO HEALTH CANADA QUESTIONS REGARDING THE

EVALUATION CRITERIA IN THE TERATOGENICITY/DEVELOPMENTAL

TOXICITY STUDY OF SUMILARV (S-31183) IN RABBITS. DATE

COMPLETED: FEBRUARY 12,1996.(VOLUME 43;NNT-80-

0033).(PYRIPROXYFEN), DACO: 4.5.2

1169747 1994, SUPPLEMENTAL DATA AND REVIEW OF ONCOGENICITY STUDY

WITH S-31183 (SUMILARV) IN MICE., DACO: 4.4.2

2704558 1994, AMENDMENTS 1 & 2 TO THE FINAL REPORT: SUMILARV -

COMBINED CHRONIC TOXICITY AND ONCOGENICITY STUDY IN RATS

WITH S-31183, MRID NO. 42178314 (original study), DACO: 4.4.4

2704559 1994, ADDENDUM TO THE FINAL REPORT: SUMILARV - COMBINED

CHRONIC TOXICITY AND ONCOGENICITY STUDY IN RATS WITH S-

31183 MRID NO 42178314, DACO: 4.4.4

References

Proposed Re-evaluation Decision - PRVD2019-10

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PMRA

Document

Number

Reference

2704560 1993, S-31183: TOXICITY STUDY BY ORAL (CAPSULE)

ADMINISTRATION TO BEAGLE DOGS FOR 52 WEEKS (ADDITIONAL

INVESTIGATION) / WITH THE FOLLOWING ATTACHED:

PYRIPROXYFEN/ DOG CHRONIC STUDY / TRANSMITTAL LETTER TO

C.I. TELLONE, VALENT, FROM T. KUMAGAI, SUMITOMO CHEMICAL

(MAR 22, 1995), DACO: 4.4.5

2704561 1994, AMENDMENT TO FINAL REPORT: ONCOGENICITY STUDY IN

MICE WITH S-31183 (SUMILARV) MRID NO. 42178310), DACO: 4.4.3

2704562 1993, METABOLISM OF [PYRIDYL-2,6-14C] PYRIPROXYFEN IN RATS,

DACO: 4.5.9

2704564 1992, SUMILARV - ACUTE INHALATION TOXICITY OF S-31183 IN RATS

SUPPLEMENTAL DATA SUPPLEMENT TO MRID # 42178304, DACO: 4.2.3

2704568 1993, ACUTE ORAL TOXICITY STUDY OF PYRIPROXYFEN

METABOLITES, 4-OH-PYR, 5-OH-PYR, DPH-PYR, POPA AND PYPAC, IN

MICE, DACO: 4.2.1

2704569 1996, Acute oral toxicity study of 2,5-OH-PY in mice, DACO: 4.2.1

2704570 1996, Acute oral toxicity study of 2-OH-PY in mice, DACO: 4.2.1

2704573 1995, REVERSE MUTATION TEST OF 2,5-OH-PY IN BACTERIAL

SYSTEMS, DACO: 4.5.4

2704574 1993, Reverse Mutation Test of Metabolites of Pyriproxyfen, 4-OH-PYR, 5-OH-

PYR, DPH-PYR, POPA AND PYPAC, in Bacterial Systems, DACO: 4.5.4

2704575 1995, Reverse mutation test of 2-OH-PY in bacterial systems, DACO: 4.5.4

2704576 1988, Two-Week Administration Study of S-31183 in Rabbits / English Version

from Japanese Original, DACO: 4.3.8

2704580 1988, Perinatal and postnatal study of S-31183 orally administered to rats /

English translation by A. Hirohashi, Sumitomo Chemical (Jan 12, 1993), DACO:

4.5.2

2704582 1988, Study by orally administration of S-31183 to rats prior to and in the early

stages of pregnancy / English translation by A. Hirohashi, Sumitomo Chemical

(Jan 22, 1993), DACO: 4.5.2

2704584 2005, Uterotropic Assay of Pyriproxyfen by Oral Route Using Juvenile Rat:

Investigation on Estrogenic Effect, DACO: 4.8

2704592 2011, Pyriproxyfen: Preliminary 4 Week Dietary Study in the Female CD-1

Mouse, DACO: 4.3.3

References

Proposed Re-evaluation Decision - PRVD2019-10

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PMRA

Document

Number

Reference

2704593 2011, Pyriproxyfen: 4 Week Dietary Immunotoxicity Study in the Female CD-1

Mouse, DACO: 4.5.15,870.78

2704596 2011, An Oral (Gavage) Dose Range-Finding Acute Neurotoxicity Study of

Pyriproxyfen T.G. in Rats, DACO: 4.5.12

2704597

2011, Hershberger Assay of Pyriproxyfen T.G. Administered Orally in Male Rats,

DACO: 4.8

2704598 2011, In vitro Inhibition Assay of Pyriproxyfen T.G. with Human Recombinant

Aromatase, DACO: 4.8

2704599 2011, In vitro Androgen Receptor Binding Assay of Pyriproxyfen T.G. with Rat

Prostate Cytosol, DACO: 4.8

2704600 2011, In vitro Steroidogenesis Assay of Pyriproxyfen T.G. with H295R Cell Line,

DACO: 4.8

2704601 2011, In vitro Estrogen Receptor Binding Assay of Pyriproxyfen T.G. with Rat

Uterine Cytosol, DACO: 4.8

2704602 2012, A Pubertal Development and Thyroid Function Assay of Pyriproxyfen T.G.

Administered Orally in Intact Juvenile/Peripubertal Female Rats, DACO: 4.8

2704603 2012, A Weight-of-Evidence of the EDSP Tier 1 Studies of Pyriproxyfen T.G.,

DACO: 4.8

2704604 2012, Effects of Pyriproxyfen on Testosterone Level and Thyroid Gland in Intact

Juvenile/Peripubertal Male Rats, DACO: 4.8

2704605 2012, A Pubertal Development and Thyroid Function Assay of Pyriproxyfen T.G.

Administered Orally in in Intact Juvenile/Peripubertal Male Rats, DACO: 4.8

2704606 2011, A 28-Day Dietary Dose Range-Finding Subchronic Neurotoxicity Study of

Pyriproxyfen T.G. in Rats, DACO: 4.5.13

2704607 2011, An Oral (Gavage) Acute Neurotoxicity Study of Pyriproxyfen T.G. in Rats,

DACO: 4.5.12

2704608 2011, A 90-Day Oral Dietary Neurotoxicity Study of Pyriproxyfen T.G. in Rats,

DACO: 4.5.13

References

Proposed Re-evaluation Decision - PRVD2019-10

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B. Additional Information Considered

i) Published Information

2.0 Human and Animal Health

PMRA

Document

Number

Reference

2831624

Bayoumi, A.E. et al, 2003, Cytotoxic effects of two antimolting insecticides

in mammalian CHO-K1 cells - Ecotoxicology and Environmental Safety,

Volume 55, Pages 19 to 23, DACO: 4.8

2831625

Kojima, Mihoko et al, 2005, Evaluation of estrogenic activities of pesticides

using an in vitro reporter gene assay - International Journal of Environmental

Health Research, Volume 15, Number 4, Pages 271 to 280, DACO: 4.8

2831626

Lamberti, Monica et al, 2014, Effects of Pyriproxyfen on Viability and

Increase of Intracellular Lipids in HepG2 Cell Line - Occupational Medicine

and Health Affairs, Volume 2, Issue 5, , DACO: 4.8

2831627

Manabe, Mari et al, 2006, Evaluation of the estrogenic activities of some

pesticides and their combinations using MtT/Se cell proliferation assay -

International Journal of Hygiene and Environmental Health, Volume 209,

Pages 413 to 421, DACO: 4.8

2857240

Thalia Velho Barreto de Araujo et al, 2017, Association between

microcephaly, Zika virus infection, and other risk factors in Brazil: final

report of a case-control study - The Lancet Infectious Diseases, Volume 18,

Number 3, Pages 328 to 336, DACO: 4.8

2857241

Raphael Parens et al, 2017, A Possible Link Between Pyriproxyfen and

Microcephaly - PLOS Currents Outbreaks. 2017 Nov 27 . Edition 1, DACO:

4.8

2857242

Maria de Fatima et al, 2016, Pyriproxyfen and the microcephaly epidemic in

Brazil - an ecological approach to explore the hypothesis of their association

- memorias do Instituto Oswaldo Cruz - Volume 111, Number 12, Pages 774

to 776, DACO: 4.8

2857243

Stefania Dzieciolowska et al, 2017, The larvicide pyriproxyfen blamed

during the Zika virus outbreak does not cause microcephaly in zebrafish

embryos - Scientific Reports volume 7, Article number: 40067 , DACO: 4.8

2857244

European Food Safety Authority, 2009, CONCLUSION ON PESTICIDE

PEER REVIEW Peer review of the pesticide risk assessment of the active

substance pyriproxyfen1 (Question No EFSA-Q-2009-00239) Issued on 21

July 2009, DACO: 12.5

2857245

United States Environmental Protection Agency, 2015, EDSP Weight of

Evidence Conclusions on the Tier 1 Screening Assays for the List 1

Chemicals, DACO: 12.5

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 72

PMRA

Document

Number

Reference

2857246

United States Environmental Protection Agency, 2017, Pyriproxyfen. Human

Health Draft Risk Assessment for Registration Review., DACO: 12.5

2857247

United States Environmental Protection Agency, 2015, Pyriproxyfen. Human

Health Risk Assessment for the Petition to Increase the Established

Tolerance in/on Tea with a U.S. Registration for Imported Pyriproxyfen

treated Tea., DACO: 12.5

Information Considered for the Dietary Exposure and Risk Assessment

A. Additional Information Considered

i) Published Information

PMRA

Document

Number

Reference

1298193

PRDD2006-04: Pyriproxyfen, September 12, 2006.

2806584

REV2017-05: Re-evaluation Project Plan for Pyriproxyfen.

2956349

US EPA Memo: Pyriproxyfen. Dietary (Food and Drinking Water) Exposure and Risk

Assessment for Registration Review, DP# 440973, August 24, 2017.

2956279

EFSA: Reasoned opinion on the modification of the existing maximum residue level

for pyriproxyfen in bananas. EFSA Journal 2016;14(2):4387, 18 pp.

doi:10.2903/j.efsa.2016.4387.

2956357

JMPR 1999: Pyriproxyfen Evaluation.

Information Considered in the Occupational and Residential Assessment

A. Studies/Information Provided by Task Forces

PMRA

Document

Number

Reference

2115788

Agricultural Reentry Task Forces (ARTF). 2008. Data Submitted by the ARTF to

Support Revision of Agricultural Transfer Coefficients. Submission #2006-0257.

References

Proposed Re-evaluation Decision - PRVD2019-10

Page 73

B. Additional Information Considered

i) Unpublished Information

PMRA

Document

Number

Reference

2449137

Krolski, M.E., 2014. Observational Study to Determine Dermal and Inhalation

Exposure to Pest Control Operator (PCO) Workers Applying Deltamethrin and/or β-

Cyfluthrin Using Hand-held Equipment in a Crack and Crevice Application. SynTech

Research Laboratory Services Stilwell, KS & Eurofins Agrosciences Services, Inc.,

GA. Bayer Report No. RGDAY016. Unpublished.

C. USEPA Residential SOPs

PMRA

Document

Number

Reference

2409268

U.S. EPA (2012a). Standard Operating Procedures for Residential

Pesticide Exposure Assessment. EPA: Washington, DC. Revised

October 2012. Section 7.

Information Considered in the Environmental Assessment

A. Additional Information Considered

Published Information

PMRA

Document

Number

Reference

1298193

PRDD2006-04: Proposed Registration Decision Pyriproxyfen

1349295

RD2007-03: Registration Decision Pyriproxyfen